Lecture notes/slides Flashcards
(127 cards)
1
Q
What is neuroscience?
A
Neuroscience is the study of all aspects of nervous system function from molecular to cellular to systems to cognitive (behavioral). The goal is to integrate across all of these levels.
2
Q
Neurons (basic)
A
Neurons function to receive, integrate and transmit information. There are ~ a hundred billion neurons in the human brain. Neurons receive an average of ~ 5,000 synaptic contacts.
3
Q
Glia (basic)
A
The term glia means glue. 2. There are three types of glia: a. Oligodendrocytes and Schwann cells wrap around the axon to provide insulation in the form of myelin. Oligodendrocytes are found in the central nervous system (CNS) and Schwann cells are found in the peripheral nervous system (PNS). b. Astrocytes provide supporting function for neurons. Astrocyte processes wrap neuronal synapses. They regulate neuronal excitability by buffering extracellular potassium (K+) ions and taking up glutamate released by neurons via glutamate transporters. Astrocytes may also provide metabolic support for neurons via endfeet that wrap the cerebrovasculature.  c. Microglia are CNS resident immune cells (phagocytes) that become activated during infection and clean up cellular debris produced by damage. 3. There are ~ (approximately) ten times more glia than neurons.
4
Q
Basic structure of a neuron
A
- Soma
2. Nucleus - Dendrites
- Axon hillock
- Axon
- Myelin (formed by oligodendrocytes [CNS] or Schwann cells [PNS])
- Node of Ranvier
- Axon Collateral
- Presynaptic terminal (contains synaptic vesicles)
- Synaptic Vesicles (contain molecules of neurotransmitter)
- Synaptic cleft
- Postsynaptic density (site of receptors)
5
Q
Functional zones of a neuron (schematic)
A
6
Q
Functional zones of a neuron (chart)
A
7
Q
What is the average resting membrane potential?
A
-65mV
8
Q
Image of hyperpolarization and depolarization
A
9
Q
Hyperpolarization vs depolarization
A
As used in neuroscience Depolarization means - the membrane voltage becomes more positive.
As used in neuroscience Hyperpolarization means - the membrane voltage becomes more negative.
1. Positive ion influx results in a depolarization.
2. Positive ion efflux results in a hyperpolarization.
- Negative ion influx results in a hyperpolarization.
- Negative ion efflux results in a depolarization.
10
Q
What is the neuronal membrane?
A
The neuronal membrane is a lipid bilayer composed of phospholipids (text figure 3.3).
- The polar phosphate heads are hydrophilic.
- The nonpolar lipid tails are hydrophobic.
- Charged ions are hydrated (surrounded by water molecules). Therefore they are attracted to hydrophilic regions and repelled by hydrophobic regions. Thus ions cannot pass through the neuronal membrane and this is what maintains the separation of charges that is essential to the RMP.
11
Q
What is an ion channel?
A
An ion channel is a protein with a pore through which ions can flow.
2. The pore has open and closed states, with the default state (no stimulation) being closed.
3. Different types of ion channels are permeable to different ions (i.e., some are permeable to sodium, some to potassium, some to chloride, some to calcium and some to multiple ions). Thus, there are sodium channels, potassium channels, chloride channels etc.
12
Q
What are the main classe of ion channels?
A
- Ligand-gated (a.k.a. neurotransmitter-gated) ion channels (a.k.a. neurotransmitter receptors).
a. The binding of the ligand (the neurotransmitter) to the receptor causes the ion channel pore to open.
b. Each type of receptor specifically binds only one type of neurotransmitter. Note for future reference: There are also chemical receptors that are not ion channels. - Voltage-gated ion channels.
a. These channels are opened and closed by changes in the voltage across the membrane. The opening and closing of these channels is dependent upon the amplitude and direction of the voltage change. - Another type of ion channels are the leak channels.
a. These channels are not gated by either voltage changes or neurotransmitters.
b. An example of a leak channel is the K+ leak channel.
c. The default state of a leak channel is open! (opposite to the other types of
channels) .
13
Q
K+ leak channel
A
A. The K+ leak channel is neither ligand-gated nor voltage-gated.
B. The default state of the K+ leak channel is open.
C. The K+ leak channel exists throughout all 4 zones of the neuronal membrane.
D. The K+ leak channel results in a high resting permeability to K+. This is a major factor in determining the RMP.
14
Q
diffusional force of K+
A
15
Q
Membrane Potential’s affect on K+
A
16
Q
What is driving force?
A
The driving force determines the rate of flux. It is the sum of the diffusion and electrostatic forces. Driving force is calculated by Vm - Eion.
17
Q
What is diffusion force?
A
Diffusion force is the force on an ion due to its concentration gradient (i.e. the ratio of extracellular to intracellular concentration of an ion). Does not change significantly under physiological conditions.
18
Q
What is electrostatic force?
A
Electrostatic force is the force on an ion produced by the membrane voltage. The amount and direction of the force is a function of the membrane voltage and the charge of the ion.
19
Q
What is driving force?
A
Driving force on an ion is the sum of the diffusion and electrostatic forces. It is calculated by the formula Vm - Eion (membrane voltage minus ionic Eion). The driving force is the force that controls the rate of ion flux IF the membrane is permeable to the ion. The ion flux thus alters the Vm. The direction of driving force tells you the direction of current flow: outward is positive, inward is negative.
20
Q
What is ion flux?
A
Ion flux is the mechanism by which membrane potential is changed. It is controlled by 1) the driving force of an ion, and 2) the permeability of the membrane to that ion.
21
Q
What is equilibrium potential?
A
Equilibrium potential (Eion) is a voltage that exactly offsets the diffusional force of the ion. It is the point where diffusion and electrostatic forces counteract each other. It is calculated by the Nernst Equation.
IMPORTANT: The membrane potential is always driven toward the Eion of the ion to which the membrane is most permeable.
22
Q
Table of ion concentrations
A
23
Q
Nernst Equation
A
Eion = 2.303 RT/zF log [ion]out/[ion]in
R = gas constant
T = absolute temperature
z = valence of the ion (charge) (i.e. + 1 for K+; F = Faraday’s constant.
+ 2 for Ca++ )
At body temperature of 37 degrees C, the Nernst equation for potassium simplifies to…
2
EK = 61.54 mV log 5/100 = 61.54 mV log (0.05) = 61.54 mV (-1.3)
= - 80mV
Below is a simplification of the first part of the Nernst Equation for key ions:
2.303 RT/zF = 61.54 mV for Na+ and K+
= - 61.54 mV for Cl-
= 61.54/2 mV (i.e., 30.77 mV) for Ca2+
24
Q
What is an action potential?
A
An action potential is an explosive depolarization of membrane potential (from -55 mV up to +40 mV - toward ENa).
25
Initiation, travel, and function of action potentials:
An action potential is initiated at the axon hillock and travels down the axon resulting in neurotransmitter release.
The function of an action potential is the rapid long distance transmission of information down a neuron.
26
Diagram of action potentials
27
What is threshold for an action potential?
Threshold is typically a depolarization of about 10 mV from RMP.
28
Characteristics of an action potential:
1. Action potentials are relatively constant in amplitude and duration (amplitude is approximately 100 mV and duration is approximately 2-3 milliseconds).
2. Action potentials are always depolarizing.
3. Action potentials are all-or-none (below threshold = none; reach threshold = all).
4. Action potentials have a threshold of initiation (which is usually approximately a 10 mV depolarization from rest).
5. Action potentials have a 2 part refractory period (time in which it is difficult or impossible to initiate another AP).
a. The absolute refractory period is a phase during which it is impossible to generate another AP. The absolute refractory period occurs during the falling phase of the AP.
b. The relative refractory period is a phase during which it is more difficult to generate another AP. The relative refractory phase occurs during the undershoot.
6. Action potentials propagate without decrement (as an AP travels down the axon, it doesn't get smaller).
29
What is the maximum conduction speed of an action potential?
The maximum conduction velocity is about 100 meters/second, but is much slower in most neurons.
30
Action potential absolute vs relative refractory period:
The absolute refractory period ends approximately 1 ms (millisecond) after the action potential begins. Therefore the maximum AP frequency is 1000 APs/s (second).
The relative refractory period ends approximately 3 ms after the action potential begins. Therefore it is difficult for neurons to generate APs at a rate greater than 333/s. (actually it is rare to see frequencies greater than 100 APs/s).
31
Mechanisms for the production of action potentials:
A. At T1, the AP threshold for initiation, a critical number of voltage-gated Na+ channels open.
B. At T2, the voltage-gated Na+ channels inactivate.
C. At T2, the voltage-gated K+ channels are opening.
D. At T3, The voltage-gated K+ channels are closing (this stops K+ efflux).
32
Factors influenceing the influx of Na+
This 40 mV voltage is the peak of the action potential. Here the Na+ channels inactivate and the K+ channels open.
33
Factors influencing K+ efflux through voltage gated K+ channels
Then the voltage-gated K+ channels close and the membrane potential (Vm) repolarizes back to rest by factors affecting the RMP.
34
image of opening and inactivation of voltage gated Na+ channels
35
characteristics of the voltage gated K+ channel
1. There is a delay to open (of about a ms).
2. The voltage-gated K+ channel continues to open and close throughout the depolarization, therefore no inactivation.
3. The continued opening and closing of the voltage-gated K+ channels underlies the relative refractory period.
36
action potential propagating down an axon
37
What is the main factor that affects conduction velocity
The main factor that affects conduction velocity is the rate of propagation of these depolarizing positive ions in front of the leading edge of the action potential.
38
What puts the action in action potential?
The opening of voltage-gated Na+ channels allows an influx of Na+ which produces depolarization, causing more voltage-gated Na+ channels to open.... This is a positive feedback system and is the action in action potential.
39
What two factors affect the rate of ion travel down the axon?
1. The internal resistance (Ri) of the axon to flow of ions.
2. The membrane resistance (Rm) of the axon to ions crossing the membrane.
40
How can conduction velocity be increased?
1. Conduction velocity is increased by increasing the axon diameter, because larger diameter axons have lower internal resistance. This is the strategy taken by invertebrates (the maximum conduction velocity in invertebrates is 20 meters/second) which sometimes have giant axons.
2. Conduction velocity can also be increased by increasing membrane resistance (Rm). This is done with myelination (by oligodendroglia or Schwann cells), and this is the strategy taken by vertebrates (maximum conduction velocity in vertebrates is ~ 100 meters/second even though the axons diameters are relatively small).
41
Why does increasing Rm (e.g., by myelination) increase conduction velocity?
1. Because without myelin, more positive ions ahead of the action potential leak out of the axon, reducing the concentration of positive ions inside the axon and thus decreasing the leading edge of depolarization. Myelin reduces this loss of positive ions to the nodes of Ranvier, therefore a larger concentration of ions is kept inside the axon, causing more depolarization and thus opening more voltage-gated sodium channels and allowing more sodium to flow into the axon...
2. The action potential thus skips from node of Ranvier to node of Ranvier (this is known as saltatory conduction).
42
Why not have the whole length of the axon ensheathed in myelin (i.e., why are there nodes)?
Because even with myelin the concentration of positive ions still decreases as the ions travel down the axon away from the origin of the action potential (the axon hillock), and at some point there wouldn't be enough of a depolarization to reach threshold.
43
What is the major reason for myelin?
The increase in action potential conduction velocity, while important, probably isn't the major reason for myelin. The major reason is probably metabolic. With myelin, the
axon
myelin sheath formed by oligodendrocyte or Schwann cell
3
location of the voltage-gated Na+ and K+ channels is restricted to the nodes of Ranvier, therefore there are fewer ions fluxing in and out of the axon, so less pumping is needed to reset the ion concentration gradients (you can get faster conduction velocity with fewer overall number of channels).
44
Sodium potassium pump image
3 sodium out and 2 potassium in
45
How much metabolic energy is use for sodium/potassium pumps?
Approximately 70% of the metabolic energy consumed by the brain is used to drive the Na+/K+ pumps (approximately 20% of all energy in the body in used by the brain).
46
What happens when two action potentials collide?
They annihilate each other. The reason is because of the absolute refractory period which follow the action potentials (one AP can’t pass through the refractory membrane produced by another AP).
47
What are PSPs?
Postsynaptic potentials initiate the action potential. Their importance is that they are a decision making or computational mechanism "deciding" whether or not an action potential should be generated.
48
Characteristics of PSPs
1. PSPs have no threshold for initiation.
2. PSPs are graded in duration.
3. PSPs are graded in amplitude.
4. PSPs can vary in sign, meaning they can be either depolarizing or hyperpolarizing. 5. PSPs have no refractory period.
6. PSPs propagate decrementally, meaning they decrease in amplitude as they travel away from the locus of initiation.
49
Two types of PSP
1. Excitatory postsynaptic potential (EPSP).
2. Inhibitory postsynaptic potential (IPSP).
50
Characteristics of EPSP
1. The EPSP is always depolarizing.
2. By definition an EPSP is any PSP that increases the probability that an action potential
will be generated.
51
Characteristics of IPSP
1. IPSPs are usually hyperpolarizing, but they can be depolarizing.
2. By definition an IPSP is a PSP that decreases the probability that an action potential
will be generated.
52
What is the mechanism for generating PSPs?
The mechanism for generating PSPs is opening of neurotransmitter gated (aka ligand gated) ion channels.
53
What is the mechanism to generate EPSPs?
The mechanism for generating an EPSP is the opening of neurotransmitter-gated (a.k.a. ligand-gated) ion channels for Na+/K+ (both ions flow through the same channel).
54
What is the mechanism to generage IPSPs?
The mechanism for generating an IPSP is the opening of transmitter-gated ion channels for K+ or for Cl- (different channels).
55
figure showing how postsynaptic potentials are initiated:
56
the major characteristics of EPSPs:
57
What are the two forms of selectivity in neurotransmitter-gated ion channels.
1. Selective for which neurotransmitter binds to their receptors.
2. Selective for the type of ions that can pass through their open channel.
58
IPSP due to opening potassium channels
59
figure depicting the generation of an IPSP via the opening of neurotransmitter-gated Cl- channels:
60
Two ways to summate EPSPs and IPSPs:
1. Temporal summation occurs when the same presynaptic axon fires multiple action potentials. This results in summated PSPs. (Text figure 5.18c)
2. Spatial summation occurs when multiple presynaptic axons fire action potentials at the same time. This results in summated PSPs. (Text figure 5.18b)
61
EPSPs and IPSPs, alone and in combination. Note also that both temporal and spatial summation are shown in this diagram.
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Differences between PSPs and APs
A. PSPs differ categorically from action potentials in every way.
1. For example, PSPs have no refractory period and action potentials do.
2. For example, PSPs are graded in amplitude and duration and action potentials are
stereotyped.
B. Some reasons why PSPs and action potentials differ:
1. PSPs have no refractory period because they are generated by the opening of neurotransmitter-gated channels in the membrane of the soma and dendrites and ligand-gated ion channels have no inactivation gate.
2. PSPs are graded in amplitude because they are generated by the opening of neurotransmitter-gated ion channels and more neurotransmitter released from the
presynaptic terminal opens more channels. There is no inactivation-gate to prevent this.
63
How are EPSPs generated?
EPSPs are generated by the opening of neurotransmitter-gated Na+/K+ ion channels.
64
What is the maximum depolarization for the EPSP and why?
The maximum depolarization for the EPSP is to -9 mV. This is because -9 mV is the average of the equilibrium potentials of Na+ and K+, the two ions to which the membrane becomes equally permeable.
65
How do ion channels drive the membrane potential to -9mV (EPSP)
In this diagram:
The depolarization is caused predominantly by an influx of Na+.
The hyperpolarization is caused predominantly by an efflux of K+.
The reversal potential is the voltage at which the dominant flow of ions changes (aka reverses) direction. If the channel is permeable to only one ion, then the reversal potential would equal the equilibrium potential for that ion.
66
The figure below shows how the driving forces on sodium and potassium at -65 mV results in a greater sodium influx than potassium efflux, thus causing depolarization.
67
Flux of Na+ and K+ through open ligand-gated Na/K channels at different voltages
68
How are IPSPs generated?
IPSPs are generated by the opening of either neurotransmitter-gated Cl- or neurotransmitter gated K+ channels.
69
What drives the membrane potential to -80 mV (IPSP)
Opening of neurotransmitter-gated channels permeable to K+ will drive the membrane potential toward -80mV (the equilibrium potential for K+).
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figure depicting the generation of an IPSP via the opening of neurotransmitter-gated Cl- channels.
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How can an IPSP be depolarizing?
Because the threshold for the generation of an action potential is -55 mV, and the equilibrium potential of Cl- is -65 mV. The definition of the IPSP is a decrease in the probability of generating an action potential. So the Cl- flux serves to clamp the membrane potential at -65 mV which will decrease the probability of generation an action potential.
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Mechanisms producing Cl- efflux
73
Do ions flow down their concentration gradient?
Ions don't flow down their concentration gradients, they flow down their electrochemical gradients (two forces which can be in the same or opposite direction).
74
How is neurotransmitter released, or how is information transduced from electrical to chemical?
The one sentence answer is the opening of voltage-gated Ca2+ channels (VGCCs)
in the terminal by an action potential allows for influx of Ca2+ into the terminal, which causes NT release.
75
What happens in an active zone?
1. In the presynaptic terminal neurotransmitter vesicles are not randomly distributed. A
subset are docked in active zones.
2. In the active zone, the vesicles fuse to the presynaptic membrane and release
neurotransmitter.
a) Some vesicles fuse with and become part of the presynaptic membrane as they release transmitter. Membrane is recovered by endocytosis (or the presynaptic terminal would become forever larger).
b) Additionally it was very recently demonstrated that other vesicles “kiss” the presynaptic membrane and briefly open a small pore through which the transmitter escapes into the synaptic cleft. The pore then closes. This is termed “Kiss and Run” neurotransmitter release.
76
Neurotransmitter release
1. In the presynaptic terminal neurotransmitter vesicles are not randomly distributed. A
subset are docked in active zones.
2. In the active zone, the vesicles fuse to the presynaptic membrane and release
neurotransmitter.
a) Some vesicles fuse with and become part of the presynaptic membrane as they release transmitter. Membrane is recovered by endocytosis (or the presynaptic terminal would become forever larger).
b) Additionally it was very recently demonstrated that other vesicles “kiss” the presynaptic membrane and briefly open a small pore through which the transmitter escapes into the synaptic cleft. The pore then closes. This is termed “Kiss and Run” neurotransmitter release.
3. Neurotransmitter crosses the synaptic cleft and binds to receptors on the postsynaptic side.
4. Near the active zone there are voltage-gated Ca2+ channels (VGCCs).
5. Although the presynaptic terminals are the main sites of NT release, as you will see, the same mechanisms can also be used by some neurons to release NT from the dendrites or the cell body.
77
illustration of the process of neurotransmitter release in a single presynaptic terminal at different times:
1. At time T1 the synaptic vesicle is docked with the presynaptic membrane. This is before the action potential has arrived at the terminal and the membrane potential is approximately -65 mV.
2. At time T2 the action potential has arrived, therefore the membrane potential is approximately +40 mV. This depolarization causes the voltage-gated Ca2+ channels to open, allowing an influx of Ca2+, and therefore an increase in the local concentration of Ca2+ near the vesicles (the concentration of Ca2+ near the vesicles rises to approximately 0.3 mM).
3. At time T3 Ca2+ causes the docked vesicles to fuse to the presynaptic terminal membrane and molecules of neurotransmitter are released into the synaptic cleft.
4. At time T4 the vesicle membrane becomes part of the terminal membrane and all the neurotransmitter in the vesicle is released or, the transmitter is released in a “kiss and run” manner.
The time all this takes is called the “synaptic delay.” However, all this happens very fast, as the synaptic delay (the time from when the AP arrives at the terminal until the voltage begins to change in the postsynaptic neuron) is only ~ 0.2 msec.
78
How do we know Ca2+ is critical for the release of neurotransmitter?
1. If the neuron is bathed is a low Ca2+ solution there is still a normal action potential but no neurotransmitter is released. This demonstrates that Ca2+ is necessary for the release of neurotransmitter.
2. If Ca2+ is directly infused into the terminal, neurotransmitter is released without an action potential. This demonstrates that Ca2+ is sufficient for the release of neurotransmitter.
79
Where are peptide neurotransmitters released from?
Peptide neurotransmitters are released from secretory granules.
1. There are no voltage-gated Ca2+ channels near the secretory granules.
2. Only a rapid barrage of many action potentials arriving at the terminal will open Ca2+
channels long enough to allow sufficient Ca2+ to enter the terminal to increase the Ca2+ concentration near the secretory vesicles sufficiently to trigger release of peptide transmitter.
80
What are the four major types of synaptic connections?
1. Axo-dendritic: Presynaptic axon synapses with postsynaptic dendrite.
2. Axo-somatic: Presynaptic axon synapses with postsynaptic soma.
3. Axo-axonic: An axon synapses another axon.
4. Dendrodendritic: A dendrite synapses with another dendrite.
There are also bi-directional synapses:
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Effects of Presynaptic Facilitation and Presynaptic Inhibition on EPSPs
An AP arriving in the main presynaptic terminal produces an EPSP. Presynaptic facilitation increases this effect and presynaptic inhibition reduces it. Presynaptic facilitation makes EPSPs bigger
Mechanisms: presynaptic facilitation increases and presynaptic inhibition decreases the amount of neurotransmitter released by the terminal onto the synapse (the recipient terminal). This is because presynaptic facilitation increases the amplitude and/or the duration of the action potential that arrives in the recipient terminal and presynaptic inhibition decreases the amplitude and/or duration of the action potential that arrives in the recipient terminal
82
Effects of Presynaptic Facilitation and Presynaptic Inhibition on IPSPs
An AP arriving in the main presynaptic terminal produces an IPSP. Presynaptic facilitation increases this effect and presynaptic inhibition reduces it. Presynaptic facilitation makes IPSPs bigger.
Mechanisms: presynaptic facilitation increases and presynaptic inhibition decreases the amount of neurotransmitter released by the terminal onto the synapse (the recipient terminal). This is because presynaptic facilitation increases the amplitude and/or the duration of the action potential that arrives in the recipient terminal and presynaptic inhibition decreases the amplitude and/or duration of the action potential that arrives in the recipient terminal
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Presynaptic inhibition and facilitation. (axo-axonic synapses)
84
What is presynaptic facilitation?
Presynaptic facilitation enhances the release of neurotransmitter from the terminal receiving the presynaptic input. Therefore the EPSP or IPSP in the postsynaptic neuron is increased. Excitatory input from the terminal producing presynaptic facilitation increases the amplitude and/or duration of the action potential in the recipient terminal. That opens more voltage gated calcium channels, producing an increase in neurotransmitter release from the recipient terminal.
85
What is presynaptic inhibition?
Presynaptic inhibition decreases (or inhibits) the release of neurotransmitter by the terminal receiving the presynaptic input. Therefore the EPSP or IPSP in the postsynaptic neuron is decreased. Inhibitory input from the presynaptic terminal decreases the amplitude and/or duration of the action potential in the recipient terminal. Because fewer voltage gated calcium are opened, this results in a decrease in neurotransmitter release.
86
Sensitization in aplysia californica
1. The gill-withdraw reflex can be sensitized, or made more sensitive to stimulation, by delivering an electric shock to the animal’s head or tail. This increased sensitivity means that a smaller stimulus is now capable of eliciting the response, or the response is more pronounced to the same strength of stimulus. How does this work?
2. The neuron activated by the head shock, named L29, forms an axo-axonic synapse onto the sensory neuron axon terminal. The neurotransmitter released by L29, serotonin (abbreviated 5-HT), activates a molecular cascade that results in more Ca2+ entry into the sensory axon terminal. Thus, the axo-axonic synapse results in presynaptic facilitation.
3. Mechanisms: The serotonin receptor activated on the sensory axon terminal is a G - protein coupled metabotropic receptor, or GPCR. We will learn more about GPCRs in lecture 9, and this serves as a nice introduction. This GPCR activates an enzyme named adenylyl cyclase, which produces a second messenger named cyclic AMP (cAMP). cAMP activates a protein kinase, PKA. Protein kinases phosphorylate target proteins. In this case, PKA phosphorylates potassium channels in the sensory neuron presynaptic terminal, closing them. Remember that reducing the permeability of the membrane to potassium will shift the Vm away from EK, resulting in a prolongation of the depolarizing action potential in the presynaptic sensory nerve terminal. Therefore, voltage-gated Ca2+ channels stay open longer, resulting in more Ca2+ entry and more
3
NT release onto the postsynaptic motor neuron, increasing its output and strengthening the gill-withdraw reflex.
87
Electrical synapse review
A. For review, a key component of chemical synapses is the synaptic vesicle with neurotransmitter. The neurotransmitter is released into the synaptic cleft and binds to receptors in the postsynaptic membrane which results in a postsynaptic potential. There is a 0.2 ms synaptic delay in this process, which is the time between the action potential reaching the terminal to the time of a postsynaptic effect.
1. Connexons are particular proteins that form a bridge between the pre and postsynaptic neurons forming pores. Many such pores comprise a gap junction electrically coupling the adjacent cells.
2. These neurons are coupled so they almost act as one, because current and small molecules can easily flow both ways. Thus, electrical synapses couple neurons both electrically and biochemically.
C. One advantage of electrical synapses is that they are much faster than chemical synapses because there is no synaptic delay.
D. Some examples of electrical synapses:
1. Some circuits (such as those involved with escape behaviors) employ electrical synapses because they are faster than chemical synapses. Therefore electrical synapses are predominant in invertebrates (e.g. crayfish escape reflex).
2. There are some dendrodendritic connections that are electrically coupled. The result of this is that the electrically coupled neurons tend to act as a single neuron. For example, they tend to generate action potentials synchronously because if one depolarizes, they all depolarize, which will increase their effect on their postsynaptic targets.

3. Electrical synapses between neurons are more prevalent in mammalian systems during development, and play a major role in astrocyte function. Astrocytes are heavily interconnected by gap junctions therefore forming a syncytium. This helps astrocytes redistribute K+ and neurotransmitters released by neurons.
4. The pore formed by the connexons can open and close so that these cells can act like a single unit or as individuals. This results in a lot of flexibility.
Neurons act together when electrically coupled via open dendro-dendritic gap junctions and act as individuals when uncoupled via the closing of gap junctions.
Dendrodendritic electrical synapses that can be open or closed.
E. So why are most mammalian synapses chemical? The reason is that a chemical input can be both excitatory and inhibitory (it is a more flexible system). The other reason is that chemical synapses are more plastic than electrical synapses, which is important for learning and memory consolidation.
88
What are connexons?
1. Connexons are particular proteins that form a bridge between the pre and postsynaptic neurons forming pores. Many such pores comprise a gap junction electrically coupling the adjacent cells.
2. These neurons are coupled so they almost act as one, because current and small molecules can easily flow both ways. Thus, electrical synapses couple neurons both electrically and biochemically.
89
What is an advantage of electrical synapses?
One advantage of electrical synapses is that they are much faster than chemical synapses because there is no synaptic delay.
90
Examples of electrical synapses:
1. Some circuits (such as those involved with escape behaviors) employ electrical synapses because they are faster than chemical synapses. Therefore electrical synapses are predominant in invertebrates (e.g. crayfish escape reflex).
2. There are some dendrodendritic connections that are electrically coupled. The result of this is that the electrically coupled neurons tend to act as a single neuron. For example, they tend to generate action potentials synchronously because if one depolarizes, they all depolarize, which will increase their effect on their postsynaptic targets.
3. Electrical synapses between neurons are more prevalent in mammalian systems during development, and play a major role in astrocyte function. Astrocytes are heavily interconnected by gap junctions therefore forming a syncytium. This helps astrocytes redistribute K+ and neurotransmitters released by neurons.
4. The pore formed by the connexons can open and close so that these cells can act like a single unit or as individuals. This results in a lot of flexibility.
91
Neurons act together when electrically coupled via open dendro-dendritic gap junctions and act as individuals when uncoupled via the closing of gap junctions.
92
Why are most mammalian synapses chemical?
The reason is that a chemical input can be both excitatory and inhibitory (it is a more flexible system). The other reason is that chemical synapses are more plastic than electrical synapses, which is important for learning and memory consolidation.
93
What are spontaneously active neurons?
Spontaneously active neurons are neurons that generate action potentials in the absence of synaptic input.
94
Below is a diagram showing single action potentials being generated spontaneously at regular intervals without synaptic input. Note the smooth “ramp potentials” between the action potentials.
95
Below is a diagram depicting spontaneous bursts of action potentials being generated at regular intervals without synaptic input.
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Evidence for spontaneously active neurons
The evidence for the existence of spontaneously active neurons is that in culture (single neuron in a dish) some cells will continue to fire. In that situation there cannot be any synaptic input to that neuron.
97
The rate of action potentials from a spontaneously active neuron can be regulated by synaptic input. For example an excitatory input may increase the rate of action potentials and an inhibitory input may decrease the rate of action potentials, as shown in the diagram below.
98
Drugs affects on turtle hearts:
A turtle heart in a dish will beat spontaneously. (The heart is spontaneously active tissue).
a. If norepinephrine (a neurotransmitter) is added to the dish, heart rate will increase. b. If acetylcholine (a neurotransmitter) is added to the dish, the heart rate will decrease.
99
The implications of the existence of spontaneously active neurons range from the cellular level to the philosophical level because...
1. Before this discovery, the reigning idea was the “stimulus-response” paradigm, which states that an organism acts only after a stimulus acts on that organism to evoke a response. By that thinking organisms just integrate stimuli and respond.
2. Now we know that organisms can generate their own activity. Stimulation isn't needed to get a response (for example, dreams and hallucinations).
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Mechanisms for the production of spontaneous activity.
1. The mechanisms are very complex, involving more than 10 types of ion channels.
2. Basically though, we just need to add some stuff to the mechanisms that we already know.
a. An example is the slow ramp depolarization toward threshold. In principle, this could be caused by a slow progressive closing of K+ leak channels, which would progressively depolarize the membrane potential towards threshold. Or, the ramp potential could be caused by a slow progressive opening of Na+ channels which would also depolarize the membrane potential.
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Are all neurons equal?
Major point. Not all neurons are created equal. They have different "personalities". The compliment of voltage gated channels in the membrane gives the neuron its personality. Each neuron has its own “electrical signature”.
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Image of a complex PSP
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For this example, there are four components (or PSPs) that can be separated and shown individually under certain pharmacological conditions. This is shown in the next figure.
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1. Each of the 4 components of the complex PSP is produced by a different receptor subtype. Two of the receptor subtypes in this example are opened by the transmitter represented by the red square and the other two are opened by the transmitter represented by the green triangle. Whether they produce EPSP or IPSP depends upon the ion selectivity of the pores. Those selective for potassium or chloride produce IPSPs and those selective for both sodium and potassium produce EPSPs. Whether the PSPs are fast or slow depends upon the receptor opening kinetics.
2. Below is a diagram depicting the mechanisms producing complex PSPs:
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Naming of receptor subtypes:
Each of the 4 receptor subtypes would be given a different name. The first part of the name is usually the transmitter it binds (e.g. glutamate) followed by R for receptor and then and numerical subscript. For example, gluR1 or gluR2 or YR1 (Y = neuropeptide Y) etc.
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What produces IPSPs and EPSPs?
The most important point is: It is NOT the neurotransmitter that produces the EPSP or IPSP. Rather, the effect of the neurotransmitter is produced by the receptor subtype that it binds to. Many transmitters produce EPSPs by binding one receptor type and IPSPs by binding a different receptor subtype.
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What is a neurotransmitter?
A neurotransmitter is a chemical released by neurons in response to depolarization,
which produces an effect (usually a rapid effect) on another neuron.
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What are peptide neurotransmitters?
1. They are chains of amino acids (which is the defining characteristic of a peptide).
2. They are synthesized solely in the soma of neurons.
3. They are released from secretory granules.
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Examples of peptide neurotransmitters:
a. Opiate transmitters (they bind to the same receptors as morphine). 1. Enkephalins
2. Endorphins
b. Neuropeptide Y (NPY)
1. NPY is the most abundant peptide transmitter in the brain.
2. It is made up of 36 amino acids and thus is one of the larger peptide transmitters. 3. NPY stimulates feeding behavior in some areas of the brain.
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What are non-peptide neurotransmitters?
1. Non-peptide neurotransmitters are smaller than peptide neurotransmitters.
2. Non-peptide neurotransmitters can be synthesized in the soma or in the terminal.
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What are some examples of non-peptide neurotransmitters?
a. Amino acid transmitters
1. Glutamate (the primary excitatory neurotransmitter in the mammalian brain).
2. gamma-amino-butyric-acid (GABA: the primary inhibitory transmitter found in the
mammalian brain).
3. Glycine (an inhibitory transmitter found mostly in the spinal cord).
b. Amines
1. Catecholamines
1. Dopamine (DA)
2. Norepinephrine (NE)
3. Epinephrine (E: which is also a hormone)
2. Acetylcholine (ACh: the neurotransmitter released at the neuromuscular junction to produce muscle contractions [in contrast it inhibits heart rate]).
3. Serotonin (5-HT: which acts on 14 known receptors subtypes, the most of any known neurotransmitter. It is considered to be an inhibitory neurotransmitter).
c. ATP (ATP is also used as a cellular source of energy).
d. Nitric oxide (NO: a gaseous molecule that can thus diffuse through the neural membrane. It can be synthesized in the soma and diffuse back to a presynaptic terminal.)
e. Endocannabinoids (they bind to the same receptors as cannabis).
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Common steps in synaptic transmission:
A. Step one is the release of neurotransmitter from the presynaptic terminal.
B. Step two is the binding of the neurotransmitter to postsynaptic receptors.
1. There are two types of receptors, the ion channels and the metabotropic receptors.
a. Opening ion channels has an electrical effect (changes membrane potential).
b. Activation of metabotropic receptors (also known as G-protein linked receptors [GPCRs] or second-messenger linked receptors) changes cell biochemistry.
a. Both receptor types have a binding site for the neurotransmitter.
b. Neurotransmitter binding to the receptor on the ion channel results in a brief change in membrane potential by allowing the flux of ions.
c. Neurotransmitter (the first messenger) binding to the G-protein linked receptor (aka, metabotropic receptor) activates a biochemical signaling cascade to produce a 2nd biochemical messenger. Second messengers can have long lasting effects.
C. Step three is inactivation of the neurotransmitter.
1. Many neurotransmitter actions need to be brief. To make this possible inactivation
mechanisms are needed.
2. One mechanism of inactivation is simply the diffusion of the neurotransmitter away from the synaptic cleft.
3. A second mechanism of inactivation is enzymatic degradation of the neurotransmitter molecules.
4. A third mechanism of inactivation is via transporters that pump the neurotransmitter away from the synaptic cleft. Transporters can pump the neurotransmitter back into the presynaptic terminal (reuptake) or into astrocytes (a type of glial cell).
D. Step four is the reuptake of the synaptic vesicle. The synaptic vesicle is pinched back off the membrane via endocytosis (the act of transmitter release is called exocytosis).
E. Step five is synthesis (or resynthesis) of neurotransmitter. Some neurotransmitters can be resynthesized in the terminal and the neurotransmitter is then repackaged into vesicles. These types of neurotransmitters are not depleted during periods of high activity (while peptide transmitters are).
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Neurotransmitter can activate receptors that are ion channels or G-protein linked.
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Drugs that affect neurotransmitter release:
1. e.g. Tetrodotoxin (TTX) blocks voltage-gated Na+ channels preventing action potentials. Therefore action potential mediated neurotransmitter release is blocked.
2. e.g. Amphetamine increases the release of dopamine (DA) and norepinephrine (NE).
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Drugs that affect receptors:
1. Agonists are drugs that bind to a receptor and mimic the effect of the endogenous neurotransmitter (and they are frequently more specific than the endogenous neurotransmitter). The endogenous transmitter itself is also an agonist at its receptor.
a. e.g. Morphine activates opiate receptors (mimicking enkephalins and endorphins).
2. Antagonists are drugs that bind to receptors and block their activity.
a. e.g. Naloxone blocks opiate receptors.
b. e.g. Curare blocks nicotinic acetylcholine receptors (the acetylcholine receptor subtype that is expressed in skeletal muscle) causing paralysis.
c. e.g. Atropine blocks muscarinic acetylcholine receptors, thereby preventing slowing of heart rate.
d. e.g. Haloperidol blocks DA receptors. Therefore too much haloperidol produces Parkinson-like symptoms.
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Drugs that affect enzymatic degradation:
Nerve gas blocks acetylcholinesterase. Consequently there is an increase in the synaptic concentration of ACh. Since ACh decreases heart rate, this stops the heart. Atropine is an antidote for nerve gas.
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Drugs that affect reuptake of neurotransmitters:
e.g. Cocaine blocks the reuptake of DA resulting in an increase in the concentration of DA in the cleft.
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Drugs that affect synthesis:
e.g. α-methyl-para-tyrosine (α-MPT) blocks the synthesis of DA, NE, and E.
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Image of notes on synthesis:
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Transport:
1. Transport from the soma to the terminal is anterograde transport. 2. Transport from the terminal to the soma is retrograde transport. 3. Anterograde transport...
a. Fast anterograde transport is about 1000 mm/day. Kinesin (which is a "motor") walks along microtubules carrying the stuff to be transported.
b. Slow anterograde transport is ~ 10 mm/day. It is the bulk flow of cytoplasm down the axon.
4. Fast retrograde transport is about 1000 mm/day. Dynein (which is a "motor") walks along microtubules carrying the stuff to be transported.
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Where is peptide synthesis?
Peptide synthesis is in the soma (rough ER to golgi where there is a budding off to form secretory granules which are transported via fast anterograde transport to the terminals).
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Why are dopamine, norepinephrine, and epinephrine called catacholamines?
Dopamine (DA), norepinephrine (NE), and epinephrine (E) are called catacholamines because they all contain the catechol nucleus:
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Why know biosynthetic pathways?
It can help with identification of specific neurons in the brain that produce and release a particular neurotransmitter. Antibodies to neurotransmitter synthesizing enzymes can be used to visualize where neurons synthesizing a certain neurotransmitter are in the brain. For example there are chemically segregated pathways for DA.
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Brain diagram:
a. Substantia nigra (in the midbrain) contains DA neurons which project to the caudate. The function of this circuit is planned motor activity. Increases in DA will result in hyperactivity.
DA neurons from substantia nigra (SN)
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b. The ventral-tegmental area contains DA neurons that project to the nucleus accumbens (involved in reward) and the cortex (involved in cognition).
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Therapeutic reasons to know biosynthetic pathways:
a. Parkinson's disease is a motor disease that is neurochemical in origin. It is caused by a progressive death of neurons in the substantia nigra projecting to the caudate. A treatment is administration of the dopamine precursor L-DOPA.
b. An overdose of L-DOPA can produce schizophrenia like symptoms. A treatment for schizophrenia is haloperidol (a DA receptor antagonist). An overdose of haloperidol leads to Parkinson's like symptoms.
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Metabotropic receptors (G-protein-coupled receptors, second-messenger-linked receptors).
A. There are three components of metabotropic receptors (Figure 6.24).
1. The receptor itself.
2. The G-proteins which are associated with the receptor. When the receptor is activated the α component of the G-protein breaks apart and interacts with effectors (as does βγ).
3. The effector proteins.
B. For the short pathway (figure 6.25), the effectors open or close ion channels to change membrane potential.
C. For the long pathway (figure 6.24 & 6.27) the effector is an enzyme which catalyzes synthesis of some protein. This allows a cell surface signal (the neurotransmitter) to affect the inside of the cell. An advantage of this system is amplification (Figure 6.30). The process where one neurotransmitter molecule activates several G-proteins which each activate several effector proteins, which each catalyze the synthesis of many proteins.
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Oligodendrocytes (CNS) vs. Schwann cells (PNS)
