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Flashcards in Neurophysiology Deck (34):
1

Nerve Physiology

Nerves produce ___ ___

You can record the electrical activity that the nerve produces using an____ 

Electricity from nerve is a ____ system.

Node: ____ inside of a membrane and the membrane has active organelles in it that are electrically ___

There is a standing (resting) potential. We can measure the difference

Its formed from the ions inside/outside the membrane and the ability of ion channels to open and close appropriately

Nerve Physiology

Nerves produce electrical pulses

You can record the electrical activity that the nerve produces using an electrode.

Electricity from nerve is a bioelectric system.

Node: electrolyte inside of a membrane and the membrane has active organelles in it that are electrically sensitive

There is a standing (resting) potential. We can measure the difference

Its formed from the ions inside/outside the membrane and the ability of ion channels to open and close appropriately

2

Review: Cable Properties of Nerve Membranes and Passive Potentials

•Base on “___” trans- Atlantic cable model

•The membrane can be modeled as a series of ____ ____ and ____.  In such a system, the voltage ____ ____ly along the membrane. 

The transmission is ____ because there are no___ elements to ___ voltage or current. 

It is only effective over ___ distances.

This kind of transmission is common in ____  fields and permits ____ of thousands of voltages (from ____).

The result triggers the ___ ___ region of the cell.   Some___ receptor potentials rely on ___ conductance.

 

There are diff kinds of electrical potentials on nerves and they all have their own fcn

Cable property: imagine wire with insulator on outside of it. Think of really long (transatlantic cable) If you put voltage at one end and measure voltage along the wire, it ____ with distance

Bc of ion channels of membrane and structure of the membrane, Nerve is like a leaky cable

As we measure down axon, the voltage decreases exponentially with distance

We can put voltages on the membrane maybe from an ___ ___ ___ or something on neurons that don’t produce AP. Just ____ membranes.

They can send the signal down _____ without a ____

Passive maintenance of the potential along the nerve for a distance.

This is the kind of transmission that often occurs with ___ ___

They don’t have to create an AP to send a signal.  Signals sent passively thru leaky channel systems.

Some of the neurons in the ____ never depolarize, just send passive potentials around that trigger off axon hillock or just ___ ___  based on passive potential

This is good for ____. Passive signals close to each other in the membrane will __ __.  That integrates that information.

This is basically a ___ potential. 

Review: Cable Properties of Nerve Membranes and Passive Potentials

•Base on “leaky” trans- Atlantic cable model

•The membrane can be modeled as a series of

parallel resistors and capacitors.  In such a system, the voltage

drops exponentially along the membrane.  The transmission is passive because there are no active elements to create voltage or current.  It is only effective over short distances.

This kind of transmission is

 common in dendritic fields and

permits integration of thousands

of voltages (from synapses).

The result triggers the axon-hillock

region of the cell.   Some sensory

receptor potentials rely on

passive conductance.

 

There are diff kinds of electrical potentials on nerves and they all have their own fcn

Cable property: imagine wire with insulator on outside of it. Think of really long (transatlantic cable) If you put voltage at one end and measure voltage along the wire, it decreases with distance

Bc of ion channels of membrane and structure of the membrane, Nerve is like a leaky cable

As we measure down axon, the voltage decreases exponentially with distance

We can put voltages on the membrane maybe from an ion channel opening or something on neurons that don’t produce AP. Just passive membranes.

They can send the signal down passively without a depolarization

Passive maintenance of the potential along the nerve for a distance.

This is the kind of transmission that often occurs with dendritic tress.

They don’t have to create an AP to send a signal.  Signals sent passively thru leaky channel systems.

Some of the neurons in the eye never depolarize, just send passive potentials around that trigger off axon hillock or just release nt based on passive potential

This is good for integrating. Passive signals close to each other in the membrane will add up. That integrates that information.

This is basically a graded potential. 

3

Review: Action potentials

A ____ voltage applied at (1) moves the membrane potential toward a threshold (-___ mV) (2).  At threshold, the __ ___ channels snap open for a brief period greatly ____ the membrane permeability to sodium,  causing the membrane potential to drive toward the Nernst equilibrium potential for sodium (___mv).  (3) ____ of sodium channels is delayed  by sodium channel ____ while ___ ___ channels continue to open (4).  Sodium channels begin to ____ (in ____ refractory period (5)) and Em moves toward  ___+ Nernst potential (6) ____ beyond the resting state, when these K channels ___  the membrane goes back to the resting potential (7). 

 

Absolute refractory period ___ ms

relative refractory period about ___ms

Action potential: Another way we can send ___ down a neuron.

Send info down the axon as an ___ or ___ depolarization of the membrane.

Membrane potential rests around -___ mV

Put in some kind of depolarizing pulse that causes the voltage to push twd a more positive level

At some point there will be a critical threshold for depolarization (-50)

When that happens the ion channels in the membrane open up. Snap open violently.

All of the Na channels open up

Equilibrium potential, if we just had Na on the cell would be +61 mV

When AP fires, all the Na channels open up and the membrane potential drives twd +61 but it never makes it

At this point we have some K channels hyperpolarizing opening up and Na channels are deactivating.

K equilibrium is a hyperpolarizing. (more negative then resting)

Drives twd -90.

To get an AP you have to get a synchrony of these channels opening and inactivation occurring

Na channels have an inactivation component so some drugs will ____ the Na ____.

Clinically useful.

(____ drugs) slow down the whole process

The Na/K pump: pumps K  in and Na out.

Inside cell has high K

Outside cell has high Na

[ ] gradient forces ions to move thru these channels down the gradient

Pump reestablishes the gradient if we fire the cell too much

Review: Action potentials

A depolarizing voltage applied at (1) moves the membrane potential toward a threshold (-55 mV) (2).  At threshold, the fast sodium channels snap open for a brief period greatly increasing the membrane permeability to sodium,  causing the membrane potential to drive toward the Nernst equilibrium potential for sodium (+61mv).  (3) Recovery of sodium channels is delayed  by sodium channel inactivation while slower potassium channels continue to open (4).  Sodium channels begin to reactivated (in relatively refractory period (5)) and Em moves toward  K+ Nernst potential (6) hyperpolarized beyond the resting state, when these K channels close the membrane goes back to the resting potential (7). 

 

Absolute refractory period .5-.8 ms relative refractory period about 2 ms

Action potential: Another way we can send information down a neuron.

Send info down the axon as an all or none depolarization of the membrane.

Membrane potential rests around -70 mV

Put in some kind of depolarizing pulse that causes the voltage to push twd a more positive level

At some point there will be a critical threshold for depolarization (-50)

When that happens the ion channels in the membrane open up. Snap open violently.

All of the Na channels open up

Equilibrium potential, if we just had Na on the cell would be +61 mV

When AP fires, all the Na channels open up and the membrane potential drives twd +61 but it never makes it

At this point we have some K channels hyperpolarizing opening up and Na channels are deactivating.

K equilibrium is a hyperpolarizing. (more negative then resting)

Drives twd -90.

To get an AP you have to get a synchrony of these channels opening and inactivation occurring

Na channels have an inactivation component so some drugs will prolong the Na inactivation. Clinically useful.

(Anticonvulsive drugs) slow down the whole process

The Na/K pump: pumps K  in and Na out.

Inside cell has high K

Outside cell has high Na

[ ] gradient forces ions to move thru these channels down the gradient

Pump reestablishes the gradient if we fire the cell too much

4

Notes on Action Potentials

The action potential is “___ or ___”, you get the whole thing or you don’t get it (unlike passive potential in this respect  and AP‘s are __ ___ for ____ information)

The action potential is like a ____ of light from a flash light. 

You can flash many times before recharging the “battery”.   _______ is the “battery” recharger and usually contributes ___ to the membrane potential during the ___ ___

Also, it is an ___-____ ____.  Very few ions really cross the membrane during the potential changes but do create significant membrane potentials which ___ further____ of ions (at the Nernst potential).

The brain runs on ___ , most of the energy used by the brain is for ___.

The refractory period at the end of the AP may serve to help keep the action potential going the __ ___down the nerve.

 

They are all or none. For that reason we don’t really integrate other potentials with AP. This is the final firing of the integrated message.

Once it reachs -50, the rest of it will happen no matter what.

Na K atpase maintains the conc grad

One AP wont get rid of this gradient on its own.

Electrochemical equiliibrium. That means that you don’t completely diffuse conc gradient on single AP. You get a bunch of them out of a single charge.

Brain runs on glucose and most of that energy

Na/K atpase uses ATP from glucose

We can monitor the fcn of the brain but looking at ___ ___

Notes on Action Potentials

The action potential is “all or none”, you get the whole thing or you don’t get it (unlike passive potential in this respect  and AP‘s are not useful for integrating information)

The action potential is like a flash of light from a flash light. 

You can flash many times before recharging the “battery”.   Na-K ATPase is the “battery” recharger and usually contributes little to the membrane potential during the action potential.

Also, it is an electro-chemical equilibrium.  Very few ions really cross the membrane during the potential changes but do create significant membrane potentials which oppose further transfer of ions (at the Nernst potential).

The brain runs on glucose, most of the energy used by the brain is for messaging.

The refractory period at the end of the AP may serve to help keep the action potential going the right way down the nerve.

 

They are all or none. For that reason we don’t really integrate other potentials with AP. This is the final firing of the integrated message.

Once it reachs -50, the rest of it will happen no matter what.

Na K atpase maintains the conc grad

One AP wont get rid of this gradient on its own.

Electrochemical equiliibrium. That means that you don’t completely diffuse conc gradient on single AP. You get a bunch of them out of a single charge.

Brain runs on glucose and most of that energy

Na/K atpase uses ATP from glucose

We can monitor the fcn of the brain but looking at glucose utilization

5

Electric Potentials on the Nerve

Threshold-the membrane potential where a____ increase in ____ to ions occurs.

Action potential-an all or nothing nerve signal that ___ travels___ distances.

Passive Potential-Changes in membrane potential that do __ ____ result in an ___ ___ and are ___ potentials effective over a ___ distance.

EPSP-___ __ ___ ___ 

IPSP-___________

Most CNS drug effects are mediated through changes in ___ ___ ___.  Drugs can increase or decrease ____ mediated by ___ ___ or via ____ or ohm’s law changes in nerve membrane function.

A few drugs may alter brain function by acting at other sites such as ___ or through actions on neuronal ___ or ____.

This puts together idea of passive potentials and action potentials.

In order to fire an action potential you may need a number of ___ ___

EPSP (Excitatory Post Synaptic Potential): one nerve talking to another and sending nt. Nt in little packets. Each packet results in a __ __ of depolarization.  If you send enough packets you can get up to___. Then automatic Na channels open and boom you get AP. Then we start to deactivate Na channels and the whole thing comes back down.

If you are in the brain and you have multiple controls (say on a dendrite for firing a particular AP) then we might have IPSPs. They ____ the neuron. One way to do that is change K conductance.Open up K conducatnce. Drives twd -90

If cell is in hyperpolarized state,  it takes more of an ____ tone to signal off

Patients who are already taking stimulants tend to be more hyperexcitable, more crazy than other patients. If you are trying to depress there nerves, it takes more treatment to get them into a calm state

EPSP is generallly a ___ ___ often created by __ ___

These EPSPs and IPSPs can add up. One right after another,,,they will cancel each other out.

You might be able to suppress neuron firing if you put enough IPSPs in time

Electric Potentials on the Nerve

Threshold-the membrane potential where a nonlinear increase in permeability to ions occurs.

Action potential-an all or nothing nerve signal that quickly travels long distances.

Passive Potential-Changes in membrane potential that do not necessarily result in an action potential and are graded potentials effective over a short distance.

EPSP-Excitatory Post Synaptic Potential

IPSP-Inhibitory Post Synaptic Potential

Most CNS drug effects are mediated through changes in neruonal action potentials.  Drugs can increase or decrease processes mediated by action potentials or via passive or ohm’s law changes in nerve membrane function.

A few drugs may alter brain function by acting at other sites such as glia or through actions on neuronal stability or existence.

This puts together idea of passive potentials and action potentials.

In order to fire an action potential you may need a number of depolarizing pulses

EPSP (Excitatory Post Synaptic Potential): one nerve talking to another and sending nt. Nt in little packets. Each packet results in a small amt of depolarization.  If you send enough packets you can get up to threshold. Then automatic Na channels open and boom you get AP. Then we start to deactivate Na channels and the whole thing comes back down.

If you are in the brain and you have multiple controls (say on a dendrite for firing a particular AP) then we might have IPSPs. They hyperpolarize the neuron. One way to do that is change K conductance.Open up K conducatnce. Drives twd -90

If cell is in hyperpolarized state,  it takes more of an excitatory tone to signal off

Patients who are already taking stimulants tend to be more hyperexcitable, more crazy than other patients. If you are trying to depress there nerves, it takes more treatment to get them into a calm state

EPSP is generallly a graded potential often created by synaptic release

These EPSPs and IPSPs can add up. One right after another,,,they will cancel each other out.

You might be able to suppress neuron firing if you put enough IPSPs in time

6

Peripheral Fibers

•The speed of neuron transmission increases with:

–Increased ___ ___ (reduces intracelluar ___).

–Increased ___ of the myelin sheath (decreases __ ___across the nerve membrane, which saves ___ because  preserves the ____ over ____ distances)

 

Increase the lumen that decreases the resistance within the neuron.

Giant squid neurons are used in neurophysiology all the time. They have huge lumens so fire off really fast

Myelin: insulator on outside of membrane

Peripheral Fibers

•The speed of neuron transmission increases with:

–Increased axon diameter (reduces intracelluar resistance).

–Increased thickness of the myelin sheath (decreases current loss across the nerve membrane, which saves energy because  preserves the voltage over longer distances)

 

Increase the lumen that decreases the resistance within the neuron.

Giant squid neurons are used in neurophysiology all the time. They have huge lumens so fire off really fast

Myelin: insulator on outside of membrane

7

Myelinated  Fiber Conduction.

•In myelinated fibers the myelin acts as an ____ with Nodes of Ranvier where the membrane is ___.

•The action potential jumps down the nerve from node to node, ____ only occurs at the nodes so its more ___,

Myelinated nerve is efficient and its fast.

We only ____ at points along the nerve called nodes of ranvier

When we fire the nerve this one may depolarize and its graded potential. If its high enough here it will be able to depolarize this node.

If the graded potential isn’t ____ too much, it can trigger off ___ in this one

That one fires off, we got a big pulse and then the next one fires and fires and fires

Instead of going down the nerve in a fuse, its ____

Myelinated  Fiber Conduction.

•In myelinated fibers the myelin acts as an insulator with Nodes of Ranvier where the membrane is exposed.

•The action potential jumps down the nerve from node to node, repolarization only occurs at the nodes so its more efficient.

Myelinated nerve is efficient and its fast.

We only depolarize at points along the nerve called nodes of ranvier

When we fire the nerve this one may depolarize and its graded potential. If its high enough here it will be able to depolarize this node.

If the graded potential isn’t degraded too much, it can trigger off firing in this one

That one fires off, we got a big pulse and then the next one fires and fires and fires

Instead of going down the nerve in a fuse, its hopping 

8

Myelinated Fibers.

•Myelination of peripheral axons.

–Coated by ____ sheaths (____), remnants of ___ ___ ___.

–Node of Ranvier – those areas ____ the areas of myelin produced by different  Schwann cells.

–___ __ are clustered at the nodes and do not exist____ the myelination.  The nodes act like ____ stations for the axon signal to move it ___ the nerve.

 

(d) The alignment of proteins subdomains in relation to morphological features of the axoglial apparatus in the PNS demonstrates that sodium channels (red in the second panel) are restricted to the node of Ranvier and are flanked by the caspr paranodal domain (red in the third panel). Potassium channels (green in the third panel) are localized distal to the caspr “collar” in the juxtaparanodal region. Schmidt-Lanterman incisures contain the myelin associated glycoprotein (green in the second panel). Adapted from Arroyo and Scherer (2000).

Liliana Pedraza, Jeffrey K. Huang,and David R. Colman1

The Corinne Goldsmith

Organizing Principles Viewpoint of the Axoglial Apparatus

Neuron, Vol. 30, 335–344, May, 2001, Copyright 2001 by Cell Press

Here is myelinated nerve

Look for Na channels with a new dye

Na channels only exist in ___ of ____

K channels are pretty much only around the nodes of ranvier too.

The only place that has these electrically active Na/K channels is at NOR

The purpose of those channels is to generate a ____ voltage that can then send the signal to the next NofR

Myelinated Fibers.

•Myelination of peripheral axons.

–Coated by Schwann sheaths (neurolemma), remnants of Schwann cell membrane.

–Node of Ranvier – those areas between the areas of myelin produced by different  Schwann cells.

–Ion channels are clustered at the nodes and do not exist under the myelination.  The nodes act like booster stations for the axon signal to move it down the nerve.

 

(d) The alignment of proteins subdomains in relation to morphological features of the axoglial apparatus in the PNS demonstrates that sodium channels (red in the second panel) are restricted to the node of Ranvier and are flanked by the caspr paranodal domain (red in the third panel). Potassium channels (green in the third panel) are localized distal to the caspr “collar” in the juxtaparanodal region. Schmidt-Lanterman incisures contain the myelin associated glycoprotein (green in the second panel). Adapted from Arroyo and Scherer (2000).

Liliana Pedraza, Jeffrey K. Huang,and David R. Colman1

The Corinne Goldsmith

Organizing Principles Viewpoint of the Axoglial Apparatus

Neuron, Vol. 30, 335–344, May, 2001, Copyright 2001 by Cell Press

Here is myelinated nerve

Look for Na channels with a new dye

Na channels only exist in nodes of ranvier

K channels are pretty much only around the nodes of ranvier too.

The only place that has these electrically active Na/K channels is at NOR

The purpose of those channels is to generate a booster voltage that can then send the signal to the next NofR

9

Action Potential Conduction

Action potential on unmyelinated nerve

-like a ___ ___. Ion channels ___ ___ the fiber.

 

Action potential on myelinated nerve

____ from Node of Ranvier to the next node of Ranvier, called “____ ____”.

 

Dendrites usually conduct by ____ potentials but in this example a “___ ___” sits at a ____ with active ion Na+ channels that boost the signal to __ __ and __ ___ (which has many active sodium ion channels).

 

Diifferent kinds of neurons in the brain

Some are unmyelinated

These have Na/K channels all along the nerve

Electric potential is like a fuse and just rolls down the nerve

If its mylenated nerveà soltatory conduction

Jumps from one node to the next

We now know that in CNS, even on dendritic trees, if you want to boost up a signal in dendritic tree so that it makes it to the axon hillock (part of nerve that ___ the ___), you can have ___ in the ___ ___ which creates a ___ and allows the signal to get down to the axon hillock

This can occur anywhere you want AP to occur

Action Potential Conduction

Action potential on unmyelinated nerve

-like a burning fuse.  Ion channels all along

 the fiber.

Action potential on myelinated nerve

hop from Node of Ranvier to the next node

of Ranvier, called “Saltatory conduction”.

Dendrites usually conduct by passive

potentials but in this example a “booster station” sits at a junction with active ion Na+ channels that boost the signal to cell body and axon hillock (which has many active sodium ion channels).

 

Diifferent kinds of neurons in the brain

Some are unmyelinated

These have Na/K channels all along the nerve

Electric potential is like a fuse and just rolls down the nerve

If its mylenated nerveà soltatory conduction

Jumps from one node to the next

We now know that in CNS, even on dendritic trees, if you want to boost up a signal in dendritic tree so that it makes it to the axon hillock (part of nerve that makes the AP), you can have channels in the dendritic tree which creates a boost and allows the signal to get down to the axon hillock

This can occur anywhere you want AP to occur

10

Axon Hillock Initiates the Axonal Action Potential

 

•Cerebellar Purkinje Cell

•NaV=Red, voltage gated ___ ___

•DAPI Stains __ __ ___

•Green=KCNQ3 type ____channels

•Merge: Cell body with axon initial segment decorated with ion channels.  This is where the action potential ____. (Note: cell bodies usually have depolarizing ____ channels.)

 

nucleic acid-binding dye 4,6-diamidino-2-phenylindole dihydrochloride (DAPI)

F: Na channels red

Q3: K channels green

Blue: Nucleus

You can see there are a lot of K channel binding in the nucleus but its also seen densely in the axon hillock region

Axon hillock has the ___ ___ for depolarization anywhere on the cell.

What we have to do is ____ all the information of dendrites and the final soln gets sent down the ___ ___ and that triggers off ___ down the cell

The cell bodies can actually____ as well.

The positive potential carrier on cell bodies is ____

More extracellular than intracellular 1000:1

Theres a couple places we see these Ca mediated currents. One is in the cell body. Other is at the ___ ___

The currents at the synaptic jcns are carried by Ca instead of Na

Axon Hillock Initiates the Axonal Action Potential

 

•Cerebellar Purkinje Cell

•NaV=Red, voltage gated sodium channel

•DAPI Stains cell bodies blue

•Green=KCNQ3 type potassium channels

•Merge: Cell body with axon initial segment decorated with ion channels.  This is where the action potential initiates. (Note: cell bodies usually have depolarizing Ca++ channels.)

 

nucleic acid-binding dye 4,6-diamidino-2-phenylindole dihydrochloride (DAPI)

F: Na channels red

Q3: K channels green

Blue: Nucleus

You can see there are a lot of K channel binding in the nucleus but its also seen densely in the axon hillock region

Axon hillock has the lowest threshold for depolarization anywhere on the cell.

What we have to do is integrate all the information of dendrites and the final soln gets sent down the axon hillock and that triggers off AP down the cell

The cell bodies can actually depolarize as well.

The positive potential carrier on cell bodies is Ca.

More extracellular than intracellular 1000:1

Theres a couple places we see these Ca mediated currents. One is in the cell body. Other is at the synaptic ending

The currents at the synaptic jcns are carried by Ca instead of Na

11

Axonal Transport

Materials from the __ __ can be transported to various locations on the cell through multiple ___

An important process is ____ transport of materials along ____.  This schematic depicts endosomes produced near the cell soma being transported by the____ protein toward the end of the ___.  Also, material ___ ___ of the membrane at the end of the ____ can be retrogradely transported toward the ____ by ____ motors.

 

Neurons are ____ manufacturing engines

It synthesizes the proteins from DNA/RNAà Golgi

Problem: Neurons are ___ ___

Have to get those proteins down the axon.

They have little ___s and little ___

Proteins are made and turned into little cargo vesicles

These use ___ for there E source

Motors walk the cargo down the axon tubule.

2 types of motors:

____: carries stuff from ___ to ___

___: ___ to ___

Axonal Transport

Materials from the cell body can be transported to various locations on the cell through multiple processes.

An important process is biomotor transport of materials along neurotubles.  This schematic depicts endosomes produced near the cell soma being transported by the kinesin protein toward the end of the axon.  Also, material pinched off of the membrane at the end of the axon can be retrogradely transported toward the nucleus by dynein motors.

Neurons are protein manufacturing engines

It synthesizes the proteins from DNA/RNAà Golgi

Problem: Neurons are really long

Have to get those proteins down the axon.

They have little tracks and little engines.

Proteins are made and turned into little cargo vesicles

These use ATP for there E source

Motors walk the cargo down the axon tubule.

2 types of motors:

Kinases: carries stuff from cell body to synapsis

Dynein: periphery to cell body. 

12

Axoplasmic Transports

•What is transported?

–___(isoform parts)

–___

–__ ___

–___ __ ___

–___ __ ___

–Stuff from ___ ___ to  ____ (____ transport) example= ____ or rabies viruses.

 

We have axon transport mechanisms in the cell that are important for maintence of the cell but also for repair of damage

Cell surface elementsà stuff from cell surface to the nuclues. That would be like damage control or garbage collecting

Sometimes stuff from gaps bw the cells, synapses or areas where there isn’t any structure, there is virus hanging out out there and these transport mechanism can...bc the membrane is always pinching off membrane and bringing it ___ the cell so that stuff gets picked up from the transport processes and gets transported back to the ____ where sometimes it can cause disease

Axoplasmic Transports

•What is transported?

–Proteins (isoform parts)

–Mitochondria

–Ion channels

–Cell surface elements

–Synaptic vesicle proteins

–Stuff from cell surface to  nucleus (retrograde transport) example= herpes or rabies viruses.

 

We have axon transport mechanisms in the cell that are important for maintence of the cell but also for repair of damage

Cell surface elementsà stuff from cell surface to the nuclues. That would be like damage control or garbage collecting

Sometimes stuff from gaps bw the cells, synapses or areas where there isn’t any structure, there is virus hanging out out there and these transport mechanism can...bc the membrane is always pinching off membrane and bringing it intot eh cell so that stuff gets picked up from the transport processes and gets transported back to the nucleus where sometimes it can cause disease

13

Peripheral fibers - _____ flow.

•Cellular elements for the axon originated in the____ ___ and travels by process known as axoplasmic flow of ___ ___

–Fast  100 to 400 mm /day

–Slow 0.25 to 3 mm/day 

–Intermediate

 

There are multiple transport mechanisms in cells. You can measure ___ __.

Some fast some slow and some in bw. 

Peripheral fibers - axoplasmic flow.

•Cellular elements for the axon originated in the cell body and travels by process known as axoplasmic flow of various speeds.

–Fast  100 to 400 mm /day

–Slow 0.25 to 3 mm/day 

–Intermediate

 

There are multiple transport mechanisms in cells. You can measure different rates Some fast some slow and some in bw. 

14

•The Importance of the Golgi Transports...

Endoplasmic reticulum and Golgi make, package and send materials down ___ ___.

Orthograde transport is used to ___ ___ ___ (___)

 

Retrograde transport used to ____ membrane elements.

Membrane ___ ___ and ____to cell or ____ .  (___) 

 

Vacher H, Trimmer J Diverse roles for auxiliary subunits in phosphorylation

dependent regulation of mammalian brain voltage-gated potassium channels.

Eur J Physiol (2011) 462:631–643

You are taking DNAà RNAà proteinsà Golgià put it on a transporter and it is transported to where it is needed.

Imagine if you take a nerve and you compress it in the middle. All the cellular elements build up on the proximal side before the constriction. Down stream there wont be any bc they  can’t go down there. That can cause ___ ___ sometimes 

•The Importance of the Golgi Transports...

Endoplasmic reticulum and Golgi make, package and send

materials down nerve processes. Orthograde transport is used to build membrane elements (Kinesin)

 

Retrograde transport used

to renew membrane elements.

Membrane pinched off and returned

to cell or nucleus .  (Dynein) 

 

Vacher H, Trimmer J Diverse roles for auxiliary subunits in phosphorylation

dependent regulation of mammalian brain voltage-gated potassium channels.

Eur J Physiol (2011) 462:631–643

You are taking DNAà RNAà proteinsà Golgià put it on a transporter and it is transported to where it is needed.

Imagine if you take a nerve and you compress it in the middle. All the cellular elements build up on the proximal side before the constriction. Down stream there wont be any bc they  can’t go down there. That can cause chronic pain sometimes 

15

Membrane Oragnelle Processing

Vacher H, Trimmer J Diverse roles for auxiliary subunits in phosphorylation

dependent regulation of mammalian brain voltage-gated potassium channels.

Eur J Physiol (2011) 462:631–643

Look at picture in red.

Pmàendocytic vesicles: sometimes we suck it back up and carry it back to the nucleus

Membrane Oragnelle Processing

Vacher H, Trimmer J Diverse roles for auxiliary subunits in phosphorylation

dependent regulation of mammalian brain voltage-gated potassium channels.

Eur J Physiol (2011) 462:631–643

Look at picture in red.

Pmàendocytic vesicles: sometimes we suck it back up and carry it back to the nucleus

16

Synapse.

•Presynaptic terminals with synaptic vesicles, synaptic cleft, postsynaptic  membrane and receptors.

•Neurotransmitters and synaptic events.

•Excitatory vs. inhibitory transmission.

 

Synapse: Where these neurons ____to each other

Gap bw 2 neurons.

Synaptic vesicles have nt material

Synaptic cleft: ____

Synapse.

•Presynaptic terminals with synaptic vesicles, synaptic cleft, postsynaptic  membrane and receptors.

•Neurotransmitters and synaptic events.

•Excitatory vs. inhibitory transmission.

 

Synapse: Where these neurons talk to each other

Gap bw 2 neurons.

Synaptic vesicles have nt material

Synaptic cleft: the space

17

Notes.

•When the action potential reaches the ___ ___ (___synaptic) it generally triggers an ___ ___ current that activates the machinery that ____ the neuro- transmitter.

•____ potential can ____ neurotransmitters too, if the potential is ___ enough.  This is common in ___ receptors.

Synaptic bouton at the___ of the____

In some cases it’s not an AP, it’s a passive potential

If its large enough to induce these Ca channels then a synapse can fire even though there is no AP to precipitate. Its just a matter of getting the voltage up high enough to where nt will be released 

Notes.

•When the action potential reaches the synaptic bouton (presynaptic) it generally triggers an inward Ca++ current that activates the machinery that releases the neuro- transmitter.

•Passive potential can release neurotransmitters too, if the potential is large enough.  This is common in sensory receptors.

Synaptic bouton at the end of the axon

In some cases it’s not an AP, it’s a passive potential

If its large enough to induce these Ca channels then a synapse can fire even though there is no AP to precipitate. Its just a matter of getting the voltage up high enough to where nt will be released 

18

Neurotransmission

Example Cholinergic

1. Vesicle ____ (From Golgi or other)

2. Transmitter ____ (Presynaptic or in vesicle)

3. Transmitter in ____ (Held by ___ gradient or ___ ___)

4. Presynaptic ___ ___ channels – Action potential triggers ____ of CA to ____neurotransmitter

5.Presynaptic auto receptors (Can___ ___)

6. Presynaptic reuptake (Different in cholinergic synapses-___ only)

7. Synapse- (A physical ___)

8. Post synaptic receptor actions- ion channels or other. Many types, these transmit the ____ to second cell.

9. Transmitter action termination- Several processes- ____, _____, destruction by ___-depends on ___ and ____.  For acetylcholine almost exclusively ___

 

Neurotransmission on a model system (Chollinergic)

This is a bad model system because Handles nt differently than all the rest of the cells

But it’s a very commmon type of sys

First need to Form vesicles and synthesize nt that needs to go into the vesicle

In the case of Ach, the action of Ach is almost entirely terminated by catabolism of Ach. In most transmitter systems you actually take the nt back up.  What you reuptake in this system is actually choline. Choline has Acetyl coA molecule attached to it to form Ach.

Then there are pumps in the ____ wall

Sometimes its an antiporter. H for Ach to go into the vesicle.

There are more than one kind of pump. This is just an ex

We’ve got the nt in the vesicle

AP comes down and causes Ca current to come into presynaptic nerve ending and then various molecules on the presynaptic nerve membrane begin to combine with molecules on the synaptic vesicles

These bind and fuse and contents of synaptic vesicle is released onto the gap (synaptic cleft)

Then the nt will diffuse to the receptors on post synaptic cell.

Nt activates some kind of events in the post synaptic cell

For Ach, we have enzyme, _____. Rips the acetyl group off of choline. Choline is not a good transmitter. Wipes out the transmitter action when it does that.

In most neurons you have these catabolic enzymes around

Many neurons have presynaptic receptors for the ____ nt they release. They are called ____

The autoreceptors regulate the ___ and ___ of nt release.

Sometimes they have ____. Like a recptor for an opiate on a chollinergic neuron. Some___ nt system can regulate the ____ of nt from this particular cell

Transporter for choline: those are called reuptake transporters. All cells have those for different nt. There are in the central part of this whole synaptic depolarization process. 

 

Neurotransmission

Example Cholinergic

1. Vesicle formation (From Golgi or other)

2. Transmitter Synthesis (Presynaptic or in vesicle)

3. Transmitter in Vesicles (Held by H+ gradient or active pumps)

4. Presynaptic Calcium ion channels – Action potential triggers influx of CA to release neurotransmitter

5.Presynaptic auto receptors (Can regulate release)

6. Presynaptic reuptake (Different in cholinergic synapses-choline only)

7. Synapse- (A physical gap)

8. Post synaptic receptor actions- ion channels or other. Many types, these transmit the action to second cell.

9. Transmitter action termination- Several processes- Catabolism, reuptake, destruction by glia-depends on cell and neurotransmitter.  For acetylcholine almost exclusively catabolism.

 

 

Neurotransmission on a model system (Chollinergic)

This is a bad model system because Handles nt differently than all the rest of the cells

But it’s a very commmon type of sys

First need to Form vesicles and synthesize nt that needs to go into the vesicle

In the case of Ach, the action of Ach is almost entirely terminated by catabolism of Ach. In most transmitter systems you actually take the nt back up.  What you reuptake in this system is actually choline. Choline has Acetyl coA molecule attached to it to form Ach.

Then there are pumps in the vesicle wall

Sometimes its an antiporter. H for Ach to go into the vesicle.

There are more than one kind of pump. This is just an ex

We’ve got the nt in the vesicle

AP comes down and causes Ca current to come into presynaptic nerve ending and then various molecules on the presynaptic nerve membrane begin to combine with molecules on the synaptic vesicles

These bind and fuse and contents of synaptic vesicle is released onto the gap (synaptic cleft)

Then the nt will diffuse to the receptors on post synaptic cell.

Nt activates some kind of events in the post synaptic cell

For Ach, we have enzyme, achesterase. Rips the acetyl group off of choline. Choline is not a good transmitter. Wipes out the transmitter action when it does that.

In most neurons you have these catabolic enzymes around

Many neurons have presynaptic receptors for the same nt they release. They are called autoreceptors.

The autoreceptors regulate the rate and degree of nt release.

Sometimes they have heteroreceptors. Like a recptor for an opiate on a chollinergic neuron. Some other nt system can regulate the release of nt from this particular cell

Transporter for choline: those are called reuptake transporters. All cells have those for different nt. There are in the central part of this whole synaptic depolarization process. 

19

Synapse-The Place Where Neurons
Communicate with Each Other

A prototype synapse diagram is in the middle.  To the left is an electron micrograph showing the corresponding structures indicated in the figure. 

In the presynaptic terminal vesicles (little vessels) containing the transmitter substances are held, waiting for an action potential to depolarize the presynaptic nerve ending. 

Depolarization of the presynaptic ending permits ___ ___ to enter the presynaptic ending, activating a ____ of proteins that pull the ____ into the presynaptic membrane and release its contents into the synaptic ___.

The transmitters diffuse across the synaptic cleft.  On the postsynaptic membrane are receiver molecules.  These may be ___ ___ ion channels or other kinds of receptors. 

Once the message is received a wide variety of changes in the post synaptic nerve can occur from ____ of the post synaptic nerve to initiating a sequence of steps that lead to a ____ of the postsynaptic nerve. The figure in the lower right is from a review discussing how certain drugs can lead to ____ of the nerves in the brain to relieve ___ ___.

Südhof TC., The presynaptic active zone.

Neuron. 2012 Jul 12;75(1):11-25.

Postsynaptic receptor density: that’s the receptor tissue

Synaptic vesicles have a variety of different proteins and machinery associated with them which allows them to be dragged into the presymaptic membrane, opened up and contents released into synaptic cleft

Highly regulated process.

There are a bunch of different proteins here that are modulating maintaining the process of delivering the nt.

Post synaptic side is also fairly complex.

There are several postsynaptic receptors on the postsynaptic side.

Nt will active some of them

These nt can cause a series of biochemical changes to occur in the cell.

We call those ___ ___ ____: Rxns that occur inside the cell following the arrival of the nt onto the post synaptic cell 

Synapse-The Place Where Neurons
Communicate with Each Other

 

A prototype synapse diagram is in the middle.  To the left is an electron micrograph showing the corresponding structures indicated

in the figure.  In the presynaptic terminal vesicles (little vessels) containing the transmitter substances are held, waiting for an action potential to depolarize the presynaptic nerve ending.  Depolarization of the presynaptic ending permits calcium ions to enter the presynaptic ending, activating a synaptosome of proteins that pull the vesicles into the presynaptic membrane and release its contents into the synaptic cleft.  The transmitters diffuse across the synaptic cleft.  On the postsynaptic membrane are receiver molecules.  These may be ligand gated ion channels or other kinds of receptors.  Once the message is received a wide variety of changes in the post synaptic nerve can occur from depolarization of the post synaptic nerve to initiating a sequence of steps that lead to a remodeling of the postsynaptic nerve. The figure in the lower right is from a review discussing how certain drugs can lead to remodeling of the nerves in the brain to relieve psychiatric depression.

Südhof TC., The presynaptic active zone.

Neuron. 2012 Jul 12;75(1):11-25.

Postsynaptic receptor density: that’s the receptor tissue

Synaptic vesicles have a variety of different proteins and machinery associated with them which allows them to be dragged into the presymaptic membrane, opened up and contents released into synaptic cleft

Highly regulated process.

There are a bunch of different proteins here that are modulating maintaining the process of delivering the nt.

Post synaptic side is also fairly complex.

There are several postsynaptic receptors on the postsynaptic side.

Nt will active some of them

These nt can cause a series of biochemical changes to occur in the cell.

We call those secondary metabolism cascades: Rxns that occur inside the cell following the arrival of the nt onto the post synaptic cell 

20

Synaptic Vesicle Proteins

Proteins for ____ - e.g VGlut1/2 loads glutamate (___ anti-porter)

Proteins for _____ - (cATPase a hydrogen ion transporter)

Proteins for ____  (VAMP, synaptotagmin)

SV2- binds ____ (target for an ____ drug)

 

VAMP-vesicle associated membrane protein

SV2-synaptic vesicle glycoprotein (target for Botulinum toxin and anticonvulsant levitriacetam)

Synaptotagmin- a calcium binding protein involved in release of synaptic vesicles

Synaptophysin, synaptogyrin- help regulate vesicle exocytosis but functions not clear yet

vATPase- ATP drive proton pump that ____ the vesicle contents. 

CSP-cystiene string protein

vGlut-vesicular Glutamate ____ protein

Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins.

Wilhelm BG, Mandad S, Truckenbrodt S, Kröhnert K, Schäfer C, Rammner B, Koo SJ, Claßen GA, Krauss M, Haucke V, Urlaub H, Rizzoli SO.

Science. 2014 May 30;344(6187):1023-8. doi: 10.1126/science.1252884.

Wen-Pin Chang1 and Thomas C. Südhof1,2,3,4

SV2 Renders Primed Synaptic Vesicles Competent for Ca2+-Induced Exocytosis

The Journal of Neuroscience, 28 January 2009, 29(4): 883-897

Synaptic vesicle proteins. There is quite a few.

Some to get nt into the vesicle

Most nt are amines (base). Some proteins are there to create an environment to acidify the inside of the vesicle.

That traps the nt inside bc its ___

There are porteins for fusion

SV2 is the one that botox binds to. It’s a ____ of synaptic transmission. If you want to paralyze someone, tie up their SV2 youre wrinkles will go away and you’ll stop breathing

Migraines from temporallis muscle being hyperpolarized. Shoot those muscles with botox to relieve headaches. 

Synaptic Vesicle Proteins

Proteins for loading - e.g VGlut1/2 loads glutamate (hydrogen anti-porter)

Proteins for acidification - (cATPase a hydrogen ion transporter)

Proteins for fusion  (VAMP, synaptotagmin)

SV2- binds Botox, (target for an anticonvulsant drug)

 

VAMP-vesicle associated membrane protein

SV2-synaptic vesicle glycoprotein (target for Botulinum toxin and anticonvulsant levitriacetam)

Synaptotagmin- a calcium binding protein involved in release of synaptic vesicles

Synaptophysin, synaptogyrin- help regulate vesicle exocytosis but functions not clear yet

vATPase- ATP drive proton pump that acidifies the vesicle contents. 

CSP-cystiene string protein

vGlut-vesicular Glutamate uptake protein

Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins.

Wilhelm BG, Mandad S, Truckenbrodt S, Kröhnert K, Schäfer C, Rammner B, Koo SJ, Claßen GA, Krauss M, Haucke V, Urlaub H, Rizzoli SO.

Science. 2014 May 30;344(6187):1023-8. doi: 10.1126/science.1252884.

Wen-Pin Chang1 and Thomas C. Südhof1,2,3,4

SV2 Renders Primed Synaptic Vesicles Competent for Ca2+-Induced Exocytosis

The Journal of Neuroscience, 28 January 2009, 29(4): 883-897

Synaptic vesicle proteins. There is quite a few.

Some to get nt into the vesicle

Most nt are amines (base). Some proteins are there to create an environment to acidify the inside of the vesicle.

That traps the nt inside bc its ionized

There are porteins for fusion

SV2 is the one that botox binds to. It’s a modulator of synaptic transmission. If you want to paralyze someone, tie up their SV2 youre wrinkles will go away and you’ll stop breathing

Migraines from temporallis muscle being hyperpolarized. Shoot those muscles with botox to relieve headaches. 

21

Synaptosome Proteins

There around ____ synaptic related proteins.  The functions of synapses are highly ____ yet may fail, resulting in ____

The images developed by Wilhelm et al 2014 demonstrate some of this complexity.  You can see a video on Youtube

Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins.

Wilhelm BG, Mandad S, Truckenbrodt S, Kröhnert K, Schäfer C, Rammner B, Koo SJ, Claßen GA, Krauss M, Haucke V, Urlaub H, Rizzoli SO.

Science. 2014 May 30;344(6187):1023-8. doi: 10.1126/science.1252884.

It’s a complex process

Synaptosome Proteins

There around 300,000 synaptic related proteins.  The functions

of synapses are highly regulated, yet may fail, resulting disease.

The images developed by Wilhelm et al 2014 demonstrate some of this complexity.  You can see a video on Youtube

Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins.

Wilhelm BG, Mandad S, Truckenbrodt S, Kröhnert K, Schäfer C, Rammner B, Koo SJ, Claßen GA, Krauss M, Haucke V, Urlaub H, Rizzoli SO.

Science. 2014 May 30;344(6187):1023-8. doi: 10.1126/science.1252884.

It’s a complex process

22

Some Pre-Synaptic proteins

Calcium ion influx triggers ____

Voltage Gated Calcium Ion channels with ____ facilitate ____ action

Synaptotagmin-___ ___ 

SNARE-complex-on ____ (VAMP-synaptobrevin)

SNAP complex-on ____ (SNAP-Complexin-Syntaxin-Munc)

These proteins + calcium attach synaptic vesicles to the cell membrane and trigger dumping of the synaptic vesicle contents-which includes ___ ___ just the transmitter.  Transmitter, ___, ___, ____, peptides, etc.)

VAMP-vesicle associated membrane protein

Synaptotagmin- a __ ___ protein involved in release of ___ ___

Synaptophysin, synaptogyrin- help regulate ___ ____ s but functions not clear yet

Munc-Mammal uncoordinated protein-needed for ____

Rab-Part of the Ras protein family –regulate synaptic ___ and binding to transports and processing ____ vesiciles

RIM- Rab3-interacting molecule

RIM-BP – RIM binding protein

 

Ca channel: allows Ca to come in and trigger off the events.

Rim proteins are _____. They interact with ____ that interacts with proteins on the synaptic vesicle

This form a commplex

Complex pulls the ____ into the cell

Some Pre-Synaptic proteins

Calcium ion influx triggers exocytosis

Voltage Gated Calcium Ion channels with RIMs facilitate Ca++ action

Synaptotagmin-Ca++ Sensor

SNARE-complex-on vesicle (VAMP-synaptobrevin)

SNAP complex-on membrane (SNAP-Complexin-Syntaxin-Munc)

These proteins + calcium attach

Synaptic vesicles to the cell membrane and trigger dumping of the synaptic vesicle contents-which includes more than just the transmitter.  Transmitter, H+, ATP, proteins, peptides, etc.)

VAMP-vesicle associated membrane protein

Synaptotagmin- a calcium binding protein involved in release of synaptic vesicles

Synaptophysin, synaptogyrin- help regulate vesicle exocytosis but functions not clear yet

Munc-Mammal uncoordinated protein-needed for exocytosis

Rab-Part of the Ras protein family –regulate synaptic function and binding to transports and processing clathrin vesiciles

RIM- Rab3-interacting molecule

RIM-BP – RIM binding protein

Ca channel: allows Ca to come in and trigger off the events.

Rim proteins are modulators. They interact with munches that interacts with proteins on the synaptic vesicle

This form a commplex

Complex pulls the vesicle into the cell

23

The Stretching Membrane Problem

If synaptic vesicles are added to thepresynaptic membrane, why doesn’t it enlarge?

 

Various molecules cause parts of the membrane to __ ___ and return to the ___ of the presynaptic membrane (____).

 

The ___molecule (or other ___) are involved in the formation of these ___ vesicles.

 

What if there is something in the __ __ (e.g. viruses) when the vesicles are formed?

They may be ___ into the interior of the neuron  (The neuron is ____ its environment). 

 

If we take this vesicles and shove them in the Presynaptic membrane, the membrane will get really big.

What happens to extra membrane material. After it binds to the presynaptic membrane, there are some molecules such as clathrin and adaptin.

These pinch off chunks of membrane and pulls them inside the cell.

Constant process of pinching and pulling

Helps maintain the shape of the membrane after its depolarized a lot

The Stretching Membrane Problem

If synaptic vesicles are added to the

presynaptic membrane, why doesn’t it enlarge?

 

Various molecules cause parts of the membrane to pinch off and return to the inside of the presynaptic membrane (endocytosis).

 

The clathrin molecule (or other adaptins)

are involved in the formation of these

endocytic vesicles.

 

What if there is something in the synaptic gap (e.g. viruses) when the vesicles are formed?

They may be absorbed into the interior of the neuron  (The neuron is tasting its environment). 

 

If we take this vesicles and shove them in the Presynaptic membrane, the membrane will get really big.

What happens to extra membrane material. After it binds to the presynaptic membrane, there are some molecules such as clathrin and adaptin.

These pinch off chunks of membrane and pulls them inside the cell.

Constant process of pinching and pulling

Helps maintain the shape of the membrane after its depolarized a lot

24

Experiment on Calyx of Held-Mammalian Auditory Giant Synapse

Electrodes placed __ and ___ synaptically

Pre is fluorescent ___

Post is fluorescent ___

If ___  function is blocked, transmitter ___ is ___

 

Recall that in Parkinsons and Alzheimers, they get transynaptic transmission of toxic material (lipofusin)

Prions can reform cellular proteins into bad prion particles.  Like a molecular infection that occurs. You can’t kill it.

Can lead to bovine spongy epelopathy.

Experiment

They looked at a neuron. The Mammalian Auditory Giant Synapse

With this system you can put an electrode in to pre and post synaptic side. Most synapses are super tiny and you could never get an electrode in. This one is big enough. They squirted dyes into one part and the other

They measured what happens when you fire off a bunch of ___


They asked: What if you prevent the cell from making nt, what happens to all that machinery involved in ____ the vesicles into the membrane and then ___ it. 


Experiment on Calyx of Held-Mammalian Auditory Giant Synapse

Electrodes placed

Pre and post

synaptically

Pre is fluorescent green

Post is fluorescent red

If mitochondrial function is

blocked transmitter

release is exhausted.

 

Recall that in Parkinsons and Alzheimers, they get transynaptic transmission of toxic material (lipofusin)

Prions can reform cellular proteins into bad prion particles.  Like a molecular infection that occurs. You can’t kill it.

Can lead to bovine spongy epelopathy.

Experiment

They looked at a neuron. The Mammalian Auditory Giant Synapse

With this system you can put an electrode in to pre and post synaptic side. Most synapses are super tiny and you could never get an electrode in. This one is big enough. They squirted dyes into one part and the other

They measured what happens when you fire off a bunch of AP


They asked: What if you prevent the cell from making nt, what happens to all that machinery involved in fusing the vesicles into the membrane and then recovering it. 

25

Capacitance measures of presynaptic membrane
Block glutamate uptake

Message: Even though the vesicles don’t have ___, they are still ___ with the membrane and ____ (shown by ____).

Most vesicles in a central nerve terminal participate in recycling.

Xue L, Sheng J, Wu XS, Wu W, Luo F, Shin W, Chiang HC, Wu LG.

J Neurosci. 2013 May 15;33(20):8820-6. doi: 10.1523/JNEUROSCI.4029-12.2013.

They found that if you measure the capacitance of the pre and post synaptic membrane, if the membrane grows you would see that as a change in ____

When you blcok nt from forming, there were no ___ ___ excitatory potentials, that’s what you expect Glu to do, is produce potential change in the post synaptic neuron

They Fired it enough that those stopped happening

But when they measured the capacitance of the membrane, it was the ____ as if it had nt in it.

This says that Even If you run out of nt, you are still recylcing the synaptic vesicles in and out of the membrane

Capacitance measures of presynaptic membrane
Block glutamate uptake

Message: Even though the vesicles don’t have neurotransmitter,

they are still fusing with the membrane and recycling (shown by capacitance).

Most vesicles in a central nerve terminal participate in recycling.

Xue L, Sheng J, Wu XS, Wu W, Luo F, Shin W, Chiang HC, Wu LG.

J Neurosci. 2013 May 15;33(20):8820-6. doi: 10.1523/JNEUROSCI.4029-12.2013.

They found that if you measure the capacitance of the pre and post synaptic membrane, if the membrane grows you would see that as a change in capacitance.

When you blcok nt from forming, there were no post synaptic excitatory potentials, that’s what you expect Glu to do, is produce potential change in the post synaptic neuron

They Fired it enough that those stopped happening

But when they measured the capacitance of the membrane, it was the same as if it had nt in it.

This says that Even If you run out of nt, you are still recylcing the synaptic vesicles in and out of the membrane

26

Lots of Presynaptic transporters

____ Transporters

glutamate  (VGLUT1-3),

acetylcholine transporter (VAChT),

monoamine transporter (VMAT1-2)

GABA transporter (VGAT)

 

____ ___ ___Transporters

Glutamate/aspartate=

Excitatory amino acid transporter (EAAT1-5)

Betaine (choline) transporter(BGT1)

Monoamine transporters:

Dopamine transporter (DAT)

Norepinephrine transporter (NET)

Serotonin transporter(SERT)

GABA transporters 1-3 (GAT1-3)

Glycine transporter type GlyT1-2

Equilibrative nucleoside (Adenosine) transporter 1-4 (ENT1-4)

 

Vesicle transporters are powered by an ___ that Drives an ___ pump. 

Transmitter exchanged for ___

 

The natureceutical St. Johns wort

blocks vesicular reuptake of many neurotransmitters.

Cocaine blocks DAT, NET and SERT.

 

Life Sci. 2003 Jun 13;73(4):461-70.

Hyperforin inhibits vesicular uptake of monoamines by dissipating pH gradient across synaptic vesicle membrane.

Roz N1, Rehavi M.

Life Sci. 2004 Oct 22;75(23):2841-50.

Hyperforin depletes synaptic vesicles content and induces compartmental redistribution of nerve ending monoamines.

Roz N1, Rehavi M.

 

There are a lot of presynaptic transporters.

Ach was different because it uptakes choline

Most of the time they uptake the actual transmitter

The basis for most of our ____ meds is that they block the ___ ___

There are a whole bunch of different transporters

Some have to do with putting ___ into the____: Vesicle Transporters

Presynaptic Reuptake Transporters: these are the ones we block with antidepressants

St. Johns Wort: ___ antidepressantà ___ uptake blocker

Lots of Presynaptic transporters

Vesicular Transporters

glutamate  (VGLUT1-3),

acetylcholine transporter (VAChT),

monoamine transporter (VMAT1-2)

GABA transporter (VGAT)

 

Presynaptic Transmitter Reuptake Transporters

Glutamate/aspartate=

Excitatory amino acid transporter (EAAT1-5)

Betaine (choline) transporter(BGT1)

Monoamine transporters:

Dopamine transporter (DAT)

Norepinephrine transporter (NET)

Serotonin transporter(SERT)

GABA transporters 1-3 (GAT1-3)

Glycine transporter type GlyT1-2

Equilibrative nucleoside (Adenosine) transporter 1-4 (ENT1-4)

 

Vesicle transporters are powered by an ATPase that

Drives an H+ pump.  Transmitter exchanged for H+.

 

The natureceutical St. Johns wort

blocks vesicular reuptake of many neurotransmitters.

Cocaine blocks DAT, NET and SERT.

 

Life Sci. 2003 Jun 13;73(4):461-70.

Hyperforin inhibits vesicular uptake of monoamines by dissipating pH gradient across synaptic vesicle membrane.

Roz N1, Rehavi M.

Life Sci. 2004 Oct 22;75(23):2841-50.

Hyperforin depletes synaptic vesicles content and induces compartmental redistribution of nerve ending monoamines.

Roz N1, Rehavi M.

There are a lot of presynaptic transporters.

Ach was different because it uptakes choline

Most of the time they uptake the actual transmitter

The basis for most of our antidepressant meds is that they block the reuptake transporter

There are a whole bunch of different transporters

Some have to do with putting nt into the vesicle: Vesicle Transporters

Presynaptic Reuptake Transporters: these are the ones we block with antidepressants

St. Johns Wort: Natures antidepressantà Massive uptake blocker

27

Other Types of Syanapses

\

A. ___ ___ Synapse, Diffusion- ____, brain

B. ____ Synapse (____receptors)

C.____ synapses-___in mammals

 

Locations of synapes

Axo-dendritic

Axo-axonic

Axo-somatic

Axo-axon hillock

Dendro-dendritic

Soma-somatic, etc

 

Ribbon synapseàhttp://journal.frontiersin.org/Journal/10.3389/fnmol.2014.00003/full

Ref

Gary Matthews & Paul Fuchs

The diverse roles of ribbon synapses in sensory neurotransmission

Nature Reviews Neuroscience 11, 812-822 (December 2010) | doi:10.1038/nrn2924

 

Other ways of transmitting stuff across membranes

Most cells in mammals are____ synapses (what we’ve been talking about)

We talked about pre and post synaptic membranes that are in a nice neat relationship, ___ to each other.

Most of the ANS we have ___ ___. What that means is transmitter is just released out into the ___ outside of the neuron and it will find its way to a receptor somewhere out there. Like a transmitter ___ going around the cell as opposed to a tight jcn.

Ribbon synapse seen in a lot of sensory neurons. We have to have really ____ firing. Like a ___ ___  with a bunch of bullets in a row.

Electric Synapse. No ___. But there are ___that are regulatable on the __synaptic and ___membrane. And they are ___ ___that the electrical signal from one can be ___ ____into the other.

In a few places...

Found in ____ nucleus of ____

Theres a lot of richness in how synapses can form

Axon to dendrite

Lots of possibilites for integration of synapses on cells. 

Other Types of Syanapses

\

A. En Passant Synapse, Diffusion- autonomic, brain

B. Ribbon Synapse (sensory receptors)

C. Electric synapses-few in mammals

Locations of synapes

Axo-dendritic

Axo-axonic

Axo-somatic

Axo-axon hillock

Dendro-dendritic

Soma-somatic, etc

 

Ribbon synapseàhttp://journal.frontiersin.org/Journal/10.3389/fnmol.2014.00003/full

Ref

Gary Matthews & Paul Fuchs

The diverse roles of ribbon synapses in sensory neurotransmission

Nature Reviews Neuroscience 11, 812-822 (December 2010) | doi:10.1038/nrn2924

Other ways of transmitting stuff across membranes

Most cells in mammals are chemical synapses (what we’ve been talking about)

We talked about pre and post synaptic membranes that are in a nice neat relationship, close to each other.

Most of the ANS we have en passant. What that means is transmitter is just released out into the space outside of the neuron and it will find its way to a receptor somewhere out there. Like a transmitter cloud going around the cell as opposed to a tight jcn.

Ribbon synapse seen in a lot of sensory neurons. We have to have really rapid firing. Like a machine gun with a bunch of bullets in a row.

Electric Synapse. No nt. But there are pores that are regulatable on the presynaptic and post membrane. And they are so close that the electrical signal from one can be directly transferred into the other.

In a few places...

Found in mesencephalic nucleus of Trigemial

Theres a lot of richness in how synapses can form

Axon to dendrite

Lots of possibilites for integration of synapses on cells. 

28

Transmitter Targets

•Ligand Gated Ion Channels-Change ____ on membrane 

G Protein Coupled receptors-Change ____  with in cell

Trans-membrane enzymes-Mediate some ____ effects

Intracellular receptors- Mediate ____  effects

 

•Post synaptic targets move message down the___ ___

Example: A post synaptic receptor for norepinephrine is called

 ___ ___ _____receptor.   Its can cause ____ of blood vessel smooth muscles.

 

•Pre synaptic ___ ___s modify the ___ of neurotransmitters

Example A presynaptic receptor for norpeinephrine is the

alpha-2 adenoreceptor.  It decreases ____ tone from the brain,

decreasing the amount of ____ released onto the blood vessels.

 

•Reverse transmitter-Released by ____-synaptic membrane to alter

 function of ____ membrane. 

Examples: __ ___ (gaseous transmitter)

Anandamide-endogenous Cannabinoid transmitter

 

Transmitters go onto targets

Sometimes theyre Ion channels that cause depolarization in the post synaptic cell

Sometimes theyre not

Sometimes the post synaptic receptor changes the intracellular metabolism inside the post synaptic cell

When you shoot in Epi, the reason you are doing that is to activate alpha 1 adenoreceptors which then cause vessels to contract

Transmitter Targets

•Ligand Gated Ion Channels-Change voltage on membrane

G Protein Coupled receptors-Change metabolism with in cell

Trans-membrane enzymes-Mediate some hormone effects

Intracellular receptors- Mediate hormone effects

 

•Post synaptic targets move message down the neuronal tract.

Example: A post synaptic receptor for norepinephrine is called

 alpha-1 adenoreceptor.   Its can cause constriction of

blood vessel smooth muscles.

 

•Pre synaptic auto-receptors modify the release of neurotransmitters

Example A presynaptic receptor for norpeinephrine is the

alpha-2 adenoreceptor.  It decreases sympathetic tone from the brain,

decreasing the amount of norepinephrine released onto the blood vessels.

 

•Reverse transmitter-Released by post-synaptic membrane to alter

 function of presynaptic membrane. 

Examples: Nitric Oxide (gaseous transmitter)

Anandamide-endogenous Cannabinoid transmitter

 

Transmitters go onto targets

Sometimes theyre Ion channels that cause depolarization in the post synaptic cell

Sometimes theyre not

Sometimes the post synaptic receptor changes the intracellular metabolism inside the post synaptic cell

When you shoot in Epi, the reason you are doing that is to activate alpha 1 adenoreceptors which then cause vessels to contract

29

Post-Synaptic Events

Intertwined Post Synaptic Cascades of Reactions

 

VDCC- Voltage Dependent Calcium Channel

Blitzer RD, Iyengar R, Landau EM.

Postsynaptic signaling networks: cellular cogwheels underlying long-term plasticity.

Biol Psychiatry. 2005 Jan 15;57(2):113-9.

https://www.youtube.com/watch?v=ZniT8xd9YxU Role of mitochondria on pulse to pulse variability in neuronal transmission

What happens when we fire all these nt onto a post synaptic membrane.

Often ___ ___ cascade of rxns that are happening intracellularly can ____

Beta adregnergic receptor for NE

Ca channel

Glu receptor

A lot of these cause changes in ___

Ca cause a number of changes, all of which lead to changes in __ ___ from all three different systems

Although we have specific receptors we can bind to, doesn’t mean that within the cell we’re not seeing some simialr changes occuring on these downstream cascade

Post-Synaptic Events

Intertwined Post Synaptic

Cascades of Reactions

 

VDCC- Voltage Dependent Calcium Channel

Blitzer RD, Iyengar R, Landau EM.

Postsynaptic signaling networks: cellular cogwheels underlying long-term plasticity.

Biol Psychiatry. 2005 Jan 15;57(2):113-9.

https://www.youtube.com/watch?v=ZniT8xd9YxU Role of mitochondria on pulse to pulse variability in neuronal transmission

What happens when we fire all these nt onto a post synaptic membrane.

Often Down stream cascade of rxns that are happening intracellularly can interact

Beta adregnergic receptor for NE

Ca channel

Glu receptor

A lot of these cause changes in Ca.

Ca cause a number of changes, all of which lead to changes in Map kinase from all three different systems

Although we have specific receptors we can bind to, doesn’t mean that within the cell we’re not seeing some simialr changes occuring on these downstream cascade

30

Receptor Dynamics
in “Substance P” receptors

 

•Unbound receptors___ the cell membrane

•Stimulated receptors clump into ____-(____)

•Receptor tachyphylaxis- 

Rapid ____

intracellular ____,

beta- arrestin, ___

•Opiate receptors are deactivated by:

a. ____ (except ____)

b. changes in __ __s and ____

c. receptor  ____ changes.

 

Receptors move in and out of membranes and this can be fast.  After activation, the receptors may be ___ ___ of the membrane. 

Opiate action can be modified by ____but also by intracelluar ____.

Once in the cell, the receptor can be___ to the cell surface or marked for ____ by the molecule ubiquitin and  transferred to lysosomes (which destroy the protein).

 

Substance P containing neuron of dorsal horn of spinal cord.

Labeled for substance P receptor. You see label all on the surface of the membrane

If we ____ the cell, and again look at it for substance P labeling, none of its on the surface anymore. Its all in the cell.

Once the cells depolarized, the receptors of the membrane have all been pulled inside the cell for ___ ____

This stops the action of the transmitter and also triggers intracellular cascades to change things inside the post synaptic cell.

This kind of process is seen for a lot of G protein coupled cells.

Receptor Dynamics
in “Substance P” receptors

 

•Unbound receptors coat the cell membrane

•Stimulated receptors clump into beads-(endocytosis)

•Receptor tachyphylaxis-

Rapid tolerance

intracellular phosphorylation,

beta- arrestin, pinocytosis

•Opiate receptors are

  deactivated by:

     a. endocytosis (except morphine)

  b. changes in second messengers and kinases

  c. receptor  phosphorylation changes.

 

 

Receptors move in and out of membranes and this can be fast.  After activation, the receptors may be pulled out of the membrane.  Opiate action can be modified by endocytosis but also by intracelluar phosphorylation.   Once in the cell, the receptor can be returned to the cell surface or marked for destruction by the molecule ubiquitin and  transferred to lysosomes (which destroy the protein).

Substance P containing neuron of dorsal horn of spinal cord.

Labeled for substance P receptor. You see label all on the surface of the membrane

If we depolarize the cell, and again look at it for substance P labeling, none of its on the surface anymore. Its all in the cell.

Once the cells depolarized, the receptors of the membrane have all been pulled inside the cell for intracellular processing

This stops the action of the transmitter and also triggers intracellular cascades to change things inside the post synaptic cell.

This kind of process is seen for a lot of G protein coupled cells.

31

Beyond the Receptor-Intracellular Reaction Cascades Lead to ___ ___

•First messenger

•Second messengers

•Third messengers-

  Kinases phosphorylators

•Nuclear activators

•Ribosomal response

•Protein response

•Tissue ____

 

Looking at the bigger picture of the effect of neurotransmitters on the cell it becomes apparent the different types of receptors can have both “___”  and “___” actions.  These changes are mediated through changes in the cell membrane, cell interior and/or the nucleus.  These connected processes are the same process that regulate the ___ of the cell.

Drugs may act at ___ site or an other but through ____ intermediary coupling many drugs can cause changes to the cell through modification of a variety of pathways.  For example the G protein coupled beta adrenergic receptor receives an extracellular message, converts it to a g protein message, which activates a cyclic AMP second messenger, this activates Protein kinase A which phosphorylates CREB.  CREB can enter the cell nucleus and act as a transcription regulator. Changing of the transcription can lead to synthesis of new RNA and then new proteins that are then transported back to the ___ ___ or the __ ___

Advanced molecular biology is filling out the picture so that  we also know that nuclear activators are ___ ___  complexes. In addition, ribosomal complexes and their persistence for producing proteins and macromolecules may also be ____.  Protein persistence is regulated by how ____they can be placed into the cell or cell membrane and how fast they are ___ or destroyed.  

 

 

When nt hits the cell surface it can trigger off a cascade of processes.

We have nt binding. May kick off a G protein

Interacts with another

Kinases can act as a switch on different proteins

They can trigger CREBP (Camp response element binding protein) and this will change nuclear tx

This leads to a change in the ribosomes which leads to change in cargo and ___ ___.

This is the basis for ____ independence and tissue ___

Beyond the Receptor-Intracellular Reaction Cascades Lead to Neural Plasticity

•First messenger

•Second messengers

•Third messengers-

  Kinases phosphorylators

•Nuclear activators

•Ribosomal response

•Protein response

•Tissue plasticity

 

 

 

Looking at the bigger picture of the effect of neurotransmitters on the cell it becomes apparent the different types of receptors can have both “local”  and “global” actions.  These changes are mediated through changes in the cell membrane, cell interior and/or the nucleus.  These connected processes are the same process that regulate the health of the cell.

Drugs may act at one site or an other but through intracelluar intermediary coupling many drugs can cause changes to the cell through modification of a variety of pathways.  For example the G protein coupled beta adrenergic receptor receives an extracellular message, converts it to a g protein message, which activates a cyclic AMP second messenger, this activates Protein kinase A which phosphorylates CREB.  CREB can enter the cell nucleus and act as a transcription regulator. Changing of the transcription can lead to synthesis of new RNA and then new proteins that are then transported back to the cell interior or the cell membrane.

Advanced molecular biology is filling out the picture so that  we also know that nuclear activators are multi-molecular complexes. In addition, ribosomal complexes and their persistence for producing proteins and macromolecules may also be regulated.  Protein persistence is regulated by how fast they can be placed into the cell or cell membrane and how fast they are removed or destroyed.  

When nt hits the cell surface it can trigger off a cascade of processes.

We have nt binding. May kick off a G protein

Interacts with another

Kinases can act as a switch on different proteins

They can trigger CREBP (Camp response element binding protein) and this will change nuclear tx

This leads to a change in the ribosomes which leads to change in cargo and cellular remodeling.

This is the basis for tolerance independence and tissue plasticity

32

Examples of Receptor Triggered Cell Plasticity

•Function ___regulation

•Function___  regulation

 

Not just receptors, here

chronic receptor block causes

increased ___ ___ ___.

 

Point: Synaptic ___ and ___ may change over time or with exposure to ___  or ___

Through these mechanisms (described on previous slide) the cell can regulate its ____ to drugs by altering the ___ ____

Source:

Gwenaelle L. Clarke, Aritra Bhattacherjee, Sarah E. Tague, Wohaib Hasan, and Peter G. Smith

Adrenoceptor Blockers Increase Cardiac Sympathetic Innervation by Inhibiting Autoreceptor Suppression of Axon Growth

The Journal of Neuroscience, September 15, 2010 • 30(37):12446 –12454

 

Number of ___ ____can be up or down regulated.

Based on how much ___ is available in the environment

We see changes in the number of receptors in the membranes

Its not just the receptors...

This was a study where they used a ____ for the nt for a particular hormone

If you go in and try to block something, the body, thru homeostatic mechanisms will ___ ___to try to get htings back to normal

Homeostatic drive to get back to normal

When they put a blocker in here, the cells ____ the receptor.

“Im not getting enough nt, so I need more receptors. I’ll get more sensitive and get back to normal”

Even more dramatic, the cells become ____. The ____ literally grow.

We have a ____ change in protein to Oppose the action of the drugs

When people withdraw from drugs, it often takes several days or weeks for the effect of withdrawl to occur. You have to go from this ____ protein state back to that. It takes time to get back to normal state.

If addicted for longer, takes ___ for them to get back to their normal fcn

Not only are we changing the receptors but we’re changing the physical structure of ____ of post synaptic membrane

Examples of Receptor Triggered Cell Plasticity

•Function Down-regulation

•Function Up- regulation

 

Not just receptors, here

chronic receptor block causes

increased nerve filaments density.

 

Point: Synaptic shape and function may change over time or with exposure to transmitters or drugs.

 

Through these mechanisms (described on previous slide) the cell can regulate its sensitivity to drugs by altering the drug receptors.

Source:

Gwenaelle L. Clarke, Aritra Bhattacherjee, Sarah E. Tague, Wohaib Hasan, and Peter G. Smith

Adrenoceptor Blockers Increase Cardiac Sympathetic Innervation by Inhibiting Autoreceptor Suppression of

Axon Growth

The Journal of Neuroscience, September 15, 2010 • 30(37):12446 –12454

Number of nt receptors can be up or down regulated.

Based on how much nt is available in the environment

We see changes in the number of receptors in the membranes

Its not just the receptors...

This was a study where they used a blocker for the nt for a particular hormone

If you go in and try to block something, the body, thru homeostatic mechanisms will oppose you to try to get htings back to normal

Homeostatic drive to get back to normal

When they put a blocker in here, the cells upregulate the receptor.

“Im not getting enough nt, so I need more receptors. I’ll get more sensitive and get back to normal”

Even more dramatic, the cells become bushier. The dendrites literally grow.

We have a physical change in protein to Oppose the action of the drugs

When people withdraw from drugs, it often takes several days or weeks for the effect of withdrawl to occur. You have to go from this increased protein state back to that. It takes time to get back to normal state.

If addicted for longer, takes longer for them to get back to their normal fcn

Not only are we changing the receptors but we’re changing the physical structure of neurons of post synaptic membrane

33

Summary

____ are the principle cell type in the nervous system, but they are supported by___ ___ and ____ which can contribute to function.

•Neurons are the i___ ____g cells of the brain.  The dendrites are usually the ___ side, information is processed mainly by____ potential integration, the ___ of which can activate the ___ ___k.  The axon hillock triggers ___ ___which travel down the ___n to the synapse.

•At the pre-synaptic nerve ending the signal usually is converted into a ___ ___ which crosses the ____ to produce changes in the ____cell body.

•The signal can be ____ of the postsynaptic membrane or may just be changes in post synaptic membrane potentials that release ___ ___  (i.e. ___ action potential, e.g. sensory receptor potentials)

Summary

•Neurons are the principle cell type in the nervous system, but they are supported by glial cells and vasculature which can contribute to function.

•Neurons are the information processing cells of the brain.  The dendrites are usually the input side, information is processed mainly by passive potential integration, the sum of which can activate the axon hillock.  The axon hillock triggers action potentials which travel down the axon to the synapse.

•At the pre-synaptic nerve ending the signal usually is converted into a chemical message which crosses the synapse to produce changes in the postsynaptic cell body.

•The signal can be depolarization of the postsynaptic membrane or may just be changes in post synaptic membrane potentials that release neuro-transmitter (i.e. no action potential, e.g. sensory receptor potentials)

34

Other Structures at the Synapse

•Presynaptic

–Calcium channels

–Pinocytosis (endocytosis)

–Auto-receptors

–Reuptake transporters

–Transmitter catabolic enzymes

–_____

 

•Postsynaptic

–Many types of receptors

•Ion channels

•GPCR

•Transmembrane enzymes

•Growth factor and hormone receptors

•“Reverse” transmitters

 

Synaptic Structures

•Hugged by glial cells which regulate:

____environment

§Transmitter ____

§Transmitter ____

•Learning can be encoded by ___ synaptic function

   

Other Structures at the Synapse

•Presynaptic

–Calcium channels

–Pinocytosis (endocytosis)

–Auto-receptors

–Reuptake transporters

–Transmitter catabolic enzymes

–Mitochondria

 

•Postsynaptic

–Many types of receptors

•Ion channels

•GPCR

•Transmembrane enzymes

•Growth factor and hormone receptors

•“Reverse” transmitters

 

 

Synaptic Structures

•Hugged by glial cells which regulate:

§Ion environment

§Transmitter catabolism

§Transmitter precursors

•Learning can be encoded by increased synaptic function