Physiology

Question 1

Compare and contrast chemical and electrical synapses

Answer 1

Chemical synapses-synaptic cleft for diffusion of neurotransmitters from pre to post synaptic neurons, action potentials from the presynaptic neuron/s must have a summation great enough to depolarize the trigger point at the axon hillock, found in brain, spinal cord, NMJ Electrical synapses- gap junctions, fast/no delay, bidirectional, connect large groups of neurons, and are found in cardiac pacemaker cells, and some smooth muscle.

Question 2

What are the steps of synaptic transmission at the NMJ?

Answer 2

1 Action potential generated which depolarizes the length of the axon to the terminal button of the presynaptic neuron 2 Ca2+ enters the presynaptic neuron *add the rest of this process within the cell 3 Synaptic vesicles dock with the outer membrane and release neurotransmitter into the synapse 4 Neurotransmitters bind to post synaptic ligand gated receptors *Ach=nicotinic or muscarinic 5 Ions exchange across the membrane 6 depolarization of the post synaptic neuron 7 AchE breaks down Ach into choline (recycled) and acetate.

Question 3

Describe the role of Ca2+ in presynaptic vesicle release

Answer 3

Ca2+ enters through voltage gated channels that can potentially be disrupted by drugs like gabapentin, and pregabalin. It activates a signaling cascade involving kinase phosphorlyation of synapsins facilitating the release of synaptic vesicles from actin within the cytoplasm Ca2+ as well as synaptotagmin then help with the fusion of the synaptic vesicle to the outer membrane allowing the release of neurotransmitters.

Question 4

Describe the roles of Synapsins, SNARES, and Synaptotagmin in the presynaptic vesicle release process

Answer 4

*make sure you can draw this out (much easier to remember) Synapsins-when non-phosphorylated hold synaptic vesicles to actin within the cytoplasm Synaptotagmin helps Ca2+ with docking of synaptic vesicles presynaptic vesicle release process- draw it out.

Question 5

Describe the reuptake of neurotransmitters and what type of transporters are involved.What else can happen to these neurotransmitters if not recycled?

Answer 5

Diffuse, degrade, or recycle AchE breaks up Ach into acetate and choline (which is recycled) Uptake transporters bring choline back into the pre synaptic neuron. 2 main transporter types to recycle neurotransmitter into the neuron: Glutamate (Na+/K+) exchange and everything else: uses (Na+/Cl-) Drug interactions: tricyclic antidepressants are SSRI, or the anticonvulsant drug carbamazapine which blocks Na+ channels. There are also vessicle transporters that use H+ for uptaking neurotransmitters into the synaptic vesicles within the neuron- monoamine VMAT, GABA VGAT, and Ach VAChT

Question 6

Describes the role of glia in synaptic transmission?

Answer 6

Glia cells also are involved in vesicle uptake of neurotransmitters and can effect synaptic transmission.

Question 7

What is MAOs role in the neuron?

Answer 7

MAO monoamine oxidase breaks down neurotransmitter intracellularly 5-HIAA is the primary urinary metabolite of serotonin

Question 8

What is lambert-eaton syndrome and what drug interaction would you compare it to?

Answer 8

Antibodies against voltage gated Ca2+ channels in the presynaptic terminals. This would have a similar effect to gabapentin, or pregabalin as they both prevent neurotransmitter release into the synaptic cleft.

Question 9

It’s found that you have a rare genetic disorder that retards the speed of SNAP-25 to the outer membrane in neurons leading to a delayed release of neurotransmitters into the synaptic cleft following an action potential. If you could manipulate this process completely how might you make up for this deficit? A) use taxol B) decrease myelination of the axon C) use neostigmine D) use MAO inhibitor

Answer 9

C is correct- neostigmine is a AchE inhibitor which would increase synaptic concentrations of Ach allowing them to act longer in the synapse. D-would increase neurotransmitter in the cytosol but the same problem would exist in it’s potential release A-lead to neuropathy D-low down the action potential

Question 10

You have a group of neurons next to the soma of a single neuron. All of them release neurotransmitters and open postsynaptic channels of this downstream neuron. The postsynaptic membrane potential changes significantly but no action potential is generated at the trigger point/axon hillock. Why? A) The change was significant but inhibitory and polarized the membrane B) The change was significant for Na+ moving into the cell C) The change was significant for Cl- moving out of the cell D) The EPSP caused hyperpolarization

Answer 10

A is correct- If a significant change was made in the postsynaptic membrane, yet no action potential was generated then the signal must have been inhibitory B-If Na+ entered the cell in a significant amount it would depolarize and generate an action potential C-If Cl- were to move out of the cell it would provide a potential in an excitatory direction/depolarizing direction D- EPSP causes depolarization. If this said IPSP caused hyperpolarization it would also be correct

Question 11

What determines whether a EPSP or IPSP will occur?

Answer 11

The type of ion that enters the neuron and the concentration or frequency of the influx (summation). Need the right type of ion, and the right amount of potential Temporal summation-one neuron with multiple EPSP in a short time frame Spacial summation-multiple neurons with EPSP around the same time.

Question 12

What’s a good example of a non-gated ion channel?

Answer 12

K+ leak channels are “open” all the time which makes them non gated. They help control the resting membrane potential

Question 13

What type of channels are on the pre and postsynaptic neuron? What are the two main receptors for Ach and how are they different?

Answer 13

Presynaptic-Voltage Gated Na+ and Ca2+ channels Postsynaptic-ligand gated (chemical) channels Ach these ligand gated channels are either muscarinic or nicotinic. The former is metabotropic (G-protein coupled) and slow/widespread effect, the later is ionotropic and fast/locally acting

Question 14

Which receptor do most anti-cholinergic drugs target and why?

Answer 14

muscarinic because nicotine targeting would lead to widespread effects. Both the sympathetic and parasympathetic nervous systems would be depressed. This could lead to respiratory failure in the diaphragm, whereas drugs acting as nicotinic agonists would prevent the muscles from relaxing-like nicotine, or nerve gas.

Question 15

What are some examples of anti-cholinergic drugs?

Answer 15

Muscle relaxants (rocuronium-act on Muscarinic receptor),

Antipsychotics

Tricyclic antidepressants (TCA) decrease reuptake of neurotransmitter (SSRI), but also bind histamine and cholinergic receptors.

Question 16

How many receptor families does serotonin have? Which are metabotropic and which are ionotropic? What are some drugs that work with serotonin?

Answer 16

7 families 1,2,4-7 metabotropic

5-HT3 is ionotropic

Drugs Triptans are 5-HT1 agonists

Ondansetron (anti-emetics/vomiting) is 5-HT3 blocker

TCA -SSRI

Question 17

What are some ligands associated with receptor tyrosine kinase (RTK)? What effects do these have on the cell in general?

Answer 17

Growth factors, cytokines, pancreatic beta cells Upon binding there are multiple ways to reg growth RTK are unsurprisingly associated with cancers

Question 18

How do RTKs work and what is their clinical relevance?

Answer 18

Ligand binding causes dimerization of the two receptor monomers Tyrosines bound are activated Tyrosines are phosphorylated They are then able to activate protein cascade systems This leads to transcription factors activation and transcriptional upregulation This is how a drug or hormone acting as a ligand can cause protein synthesis and effect change in the body.

Question 19

How do you maximize conduction velocity?

Answer 19

Increase the diameter of the axon Myelination- Increases the membranes resistance to loosing charge, and decreases its capacity to hold charge across the membrane. Make it easier to charge the membrane- increase density/sensitivity of receptors near the trigger point/axon hillock. Have more neurons sum their potentials (spatially)

Question 20

How does saltatory conduction work?

Answer 20

Na+ depolarizes the axon with an influx of Na+ which then is trapped inside the axon by the myelin. The Na+ diffuses down the axon and then depolarizes the node of ranvier which is unmyelinated. The spacing is such that the concentration of Na+ is high enough to depolarize the node when it arrives; releasing additional Na+. Back flow signaling is inhibited by the absolute refractory period which is indicative of hyperpolarization in that region.

Question 21

Describe some of the important features of the choroid plexus

Answer 21

Only the epithelial cells of the choroid plexus present a barrier to the flow from the blood to the formation of CSF.

Blood flow through the choroid plexus is higher than even the kidneys at 3mL/min/g.

Transport of Na+, Cl-, HCO3-, and H2O through the epithelial cells.

Question 22

Contrast vasogenic and cytotoxic brain edema

Answer 22

Vasogenic edema_ (most common)._

This is caused by increased permeability of brain capillary endothelial cells which leads to increased volume of extracellular fluid/CSF.

Cytotoxic edema is when injured neurons, glia, or endothelial cells swell.

This occurs after hypoxia from asphyxia or global cerebral ischemia after cardiac arrest.

Failure of the Na+/K+ ATP-dependent pump–> allows Na+ and thus H20 to accumulate within cells.

Question 23

What space does CSF flow through and where is it absorped?

Answer 23

Subarachnoid space

Superior saggital sinus, via arachnoid granulations which allow one way flow into the venous system

Question 24

Describe the function of the CSF?

Answer 24

The brain weighs 1400-1500 g in air but effectively only 50 g when suspended in the CSF.

Removal of brain metabolites from brain interstitial fluid to venous sinuses.

Regulates brain tissue. CSF aka ECF of brain

The pH of the CSF influences: pulmonary ventilation and cerebral blood flow for homeostasis.

Question 25

Describe the blood brain barrier

Answer 25

The blood brain barrier is made up of endothelial cells with tight junctions and supported by astrocyte feet (glia limitans) which surround the endothelial cells.

Transport molecules are the main way substances travel through the barrier: i.e: glucose, AA

Question 26

What’s the Monroe Kellie doctrine?

Answer 26

Simple idea that the volume of the skull can’t increse in size (unless you’re a kid), so increasing the volume of fluids will increase pressure

Question 27

Contrast the three ways to produce hydrocephalus

Answer 27

Increase in volume of cerebral ventricles

Impaired absorption

Can cause communicating hydrocephalus, which is the enlargement of the entire ventricular system without affecting flow.

Causes: subarachnoid hemorrhage (which arteries?), trauma or bacterial meningitis.

Normal pressure hydrocephalus can produce symptoms such as dementia, urinary incontinence, and apraxia. (wet, weird, …?) Presents with episodic elevations in pressure.

Obstruction

Tumors, congenital malformations, scarring can cause obstruction. esp-aquaduct of sylvius

Question 28

Link headache to changes in vasculature, CSF, or cranial innervation

Answer 28

General-Headache is likely to be caused by activation of nociceptors from changes in the meninges and vascular changes.

Specific examples-

Pain from a loss of CSF: imbalance in CSF pressure

Pain from inflammation of the meninges

Pain from stretching of the dura (tumors, hydrocephalus)

Pain from migraines: vasodilation and stretching of vessels are involved

Pain from dental infection and sinusitis are referred along the trigeminal nerve.

Pain from reading: Tonic spasm of the ciliary muscle in the eye; orbital headaches.

Question 29

Glia cells perform what function at a C fiber synapse?

Answer 29

C-fibers as well as alpha delta fibers are nociceptor neurons that use glutamate as their neurotransmitter.

The role of glia cells in this context is to uptake glutamate using a Na+/K+ transporter, converting it to glutamine and then sending it back into the presynaptic neuron to be recycled.

*(other neurotransmitters use Na+/Cl-, and synaptic vesicles use H+)

Question 30

How many receptors does glutamate have to bind to postsynaptically? What type of receptors are these?

Answer 30

4 total

3 ionotropic: include AMPA, and NMDA

1 metabotropic (G-protein coupled)

Question 31

How might long term potentiation be related to learning in the brain?

How might long term depression be related to forgetfullness?

Answer 31

LTP-essentially makes a postsynaptic neuron more sensitive to incomming signals/neurotransmitters and also encourages their release. This sensitization makes for a stronger connection between the two, and maybe related to learning in the brain.

If contrasted with STP this would decrese the stregth of the connection between two neurons until the point where there would be no connection at all.

Question 32

Describe how Long term potentiation works?

LTD?

Answer 32

LTP- occurs when there is a high Ca2+ influx in the postsynaptic neuron due to ionotropic NMDA receptor activation (by glutamate). This influx of Ca2+ activates signaling cascades through phosphorylation and does 2 important things:

1) generates more receptors
2) release NO to act on the presynaptic neuron thereby increasing neurotransmitter release

LTD is similar but is stimulated by low levels of Ca2+ which activates postsynaptic phosphatases which presumably dephosphorylate proteins that would otherwise modulate NMDA.

Question 33

You’re a yound white female who’s concerned about osteoporosis. You decide to start suplimenting with Ca2+ without consulting anyone, and start taking 3x the UI level each day. How might your neurvous system respond to this?

A) Neuron depression

B) Neuron excitiation

C) Increased osteoclast activity

Answer 33

A-neuron depression

Why? b/c Ca2+ blocks Na+ channel preventing depolarization, and intracellular K+ channels leading to hyperpolarization.

Question 34

Which of the following states will lead to a more hyperexcitable neuron?

A) Hypokalemia

B) hyperkalemia

C) Hypercalcemia

Answer 34

B-hyperkalemia

Hyperkalemia = excess K+ in the blood and will decrease the flow of K+ diffusing through non-gated ion channels in the cell membrane (leakage channels). The increase + charge of the retained K+ will depolarize the cell, and will either make it more excitable, or trigger an action potential. The latter option may come at the expense of the cell remaining in a depolarized state. If it doesn’t hyperpolarize, it will be unable to trigger another action potential; as the VG Na+ channels inactivation gate will not be able to reset.

Hypocalcemia also leads to an excitable state but wasn’t an option.

Question 35

Your sickle cell patient frequently has ischemia in various parts of their body leading to localized hypoxia. If enemia results in this region what’s the likely cause?

Answer 35

hypoxia is a lack of oxygen, which is necissary in most cells of the body in the ETC in order to make ATP through oxidative phosphorylation. No ATP means no Na/K ATPase/pump.

The result in an incresed intracellular Na+ level, increased cellular water retention, and eventual cell lysis.

Question 36

explain the length and time constant for neurons and how they are typically optimized

Answer 36

length=Rm/IR

Time=Rm x Cm

Membrane resistance/RM-increased by myelin (resistance to loosing ions)

Membrane Capacitance/Cm-lower the better, quickly charges thus decreases time constant more than RM increases it

Internal resistance-increased axon diameter will decrease IR

Question 37

How is cerebral perfusion pressure measured?

Answer 37

CPP=MAP-ICP

cerebral perfusion pressure=mean arterial pressure-intracranial pressure

High ICP means low perfussion pressure

High MAP means high perfusision pressure

Determine which is higher to determine pressure.

Question 38

How does intracranial pressure change under the following conditions?

1 Hypercapnia

2 Hypocapnia

3 Increasing MAP

4 Decresing MAP

5 Acidosis

6 Alkalosis

Answer 38

1 increase

2 decrease

3 decrease

4 increase

5 increase

6 decrease

Question 39

What is autoregulation, active hyperemia, and reactive hyperemia and how does the cerebral circulation demonstrate all three?

Answer 39

autoreg-intrinsic control

Myogenic hypothesis: Vascular smooth muscles of the arterioles contract when stretched

Active hyperemia

metabolic hypothesis- increase in flow in response to metabolic demand. Example: increase in metabolitis leads to vasodilation and increase in flow; many metabolites are vasodilators.

Reactive hyperemia

Longer periods of occlusion lead to larger transient increases in blood flow.

Question 40

How does ischemia lead to cell damage in neurons; what role does glutamate play in this?

Answer 40

Lack of O2=lack of ATP

=lack of ATPase pumps

=influx of Na+ depolarization, swollen cells, and influx of Ca2+

Ca2+ causes all sorts of problem

Depolarization releases glutamate which overactivates it’s receptors such as NMDA which facilitate Ca2+ influx and further damage.

If local astroglia are also starved of O2 they can’t sequester the glutamate and thus it can have broader affects on neighbouring neurons.

Question 41

What’s happening with the cushing reaction/triad?

Answer 41

Basically there is a fight between the systemic circulation and the local regulation of the brains vasculature. There are contradictory signals being sent about how to regulate blood flow.

Question 42

What is excitotoxicity and whats the rationale for why certain interventions may work to protect against it?

Answer 42

Excitotoxicity is when neurons are excited by stimulatory neurotransmitters in a dysregulated way leading to hyperexcitability and cellular damage from Ca2+ influx.

Protection comes from Na/K pumps and Ca2+ binding proteins

also antioxidants, growth factors, and glutamate receptor blockers