Medical Physiology Block 2 Week 2

Question 1

List the electrical and chemical steps in synaptic transmission, from arrival of an action potential in the nerve terminal to activation of receptors on the postsynaptic cell.

Answer 1

Electrical steps: opening of voltage-gated sodium channels followed by opening of voltage-gated potassium channels (opening of voltage-gated calcium channels at presynaptic terminal); Chemical steps: graded potentials received by dendrites and synaptic vesicles being released into the synaptic cleft

Question 2

Compare and contrast the fast excitatory postsynaptic potentials (EPSPs) produced by acetylcholine at the neuromuscular junction, and by glutamate in the central nervous system. Discuss (a) the receptor types involved, (b) the ionic selectivity of the channels opened, (c) the typical quantal content, (d) the duration of the EPSP, and (e) the mechanism of removal of transmitter from the synaptic cleft.

Answer 2

NMJ: Ach, nicotinic Ach receptors (permeable to K and Na), 1-10 msec duration, terminated by acetylcholinesterase, about 100 quanta released per event;

CNS: Glutamate, NMDA (also permeable to calcium) and AMPA receptors, AMPA = 1-10 msec duration and NMDA = 10-100 msec duration, terminated by diffusion, sensitization or reuptake, about 1 quanta released per event

Note PSPs from both these conditions are generated by calcium-dependent exocytosis

Question 3

Compare and contrast the functions and mechanisms of synaptic potentials mediated by AMPA- vs. NMDA-type glutamate receptors. Include the time course, the voltage dependence, the ion selectivity, and the pharmacology of the responses.

Answer 3

AMPA receptors: fast (small conductance), voltage independent, permeable to mostly K and Na, point to point transmission of information; NMDA receptors: slower, requires depolarization and glutamate binding (associative), voltage-dependent magnesium block, important in synaptic plasticity

Question 4

Explain the mechanisms underlying fast, short term (millisecond-second) synaptic plasticity of EPSPs.

Answer 4

Low frequency stimulation (depression): reduction in quantal content (probably occurring in events utilizing large quantities of quanta), depletion of readily releasable vesicles; high frequency stimulation (facilitation): increase in quantal content (probably occurring in events where few quanta are being released), increase in presynaptic terminal calcium

Question 5

Explain why long-term plasticity is attractive as a mechanism underlying learning and memory.

Answer 5

Associative: glutamate + depolarization (use dependent and requires many different neurons firing at the same time to cause depolarization); presynaptic Ca2+ influx and postsynaptic postsynaptic NMDA receptor binding

Question 6

Explain the mechanisms underlying long-term (minutes-hours) synaptic plasticity, including long-term potentiation (LTP) of fast EPSPs on pyramidal neurons in the CA1 region of the hippocampus.

Answer 6

Glutamate release (pre) + depolarization (post) leads to Ca2+ influx (NMDAR) = LTP (actives calcium-calmodulin dependent kinase and increase the number of AMPA receptors at the postsynaptic membrane); LTD = phosphatases are reduction in the number of AMPA receptors at postsynaptic membrane

Question 7

List several neurotransmitters that can activate ligand-gated ion channels. Describe the evolutionary relationships among their receptors.

Answer 7

Glutamate, Ach, serotonin, ATP, GABA (brain), glycine (spinal cord)

Question 8

State the ionic mechanism of fast inhibitory postsynaptic potentials (IPSPs) mediated by Gamma-aminobutyric acid (GABA) in the central nervous system

Answer 8

Chloride conductance through GABA receptors lasting 10-100 msec, followed by termination through diffusion or reuptake (1 quanta released through calcium dependent exocytosis)

Question 9

Explain why the a fast IPSP is inhibitory, even though the change in membrane potential is generally small and may even be a depolarization.

Answer 9

GABA-mediated IPSPs are inhibitory because the reversal potential of Chloride-selective channels is negative to the threshold of firing an action potential (IPSPs and EPSPs are differentiated by whether the reversal potential of a channel in above or below threshold)

Question 10

Compare and contrast the mechanisms of release and action of nitric oxide (NO) to other neurotransmitters.

Answer 10

Not released by Ca2+-dependent exocytosis; Acts primarily via cGMP, protein kinase G; Can also chemically modify proteins

Question 11

List several neurotransmitters that can activate G protein-coupled receptors.

Answer 11

Endocannabinoids, catecholamines (Dopamine, NE, E), peptides, glutamate, GABA, Ach

Question 12

What is the difference in morphology of excitatory v. inhibitory neurons? What is the exception?

Answer 12

Excitatory- projection neuron; inhibitory- interneuron; exception Purkinje cells (inhibitory projection neurons)

Question 13

Explain how neurons can release multiple neurotransmitters. Explain how release from large vs. small synaptic vesicles can be differentially regulated.

Answer 13

At low frequencies, neurons only release small synaptic vesicles; At high frequencies, neurons release both small synaptic vesicles and large dense core vesicles (large vesicles are released with slower kinetics and require significantly more intracellular calcium)

Question 14

Describe the biochemical pathways involved in slow (G protein-mediated) synaptic actions in the nervous system.

Answer 14

Binding of a ligand to a receptor activates G proteins, which themselves can modulate channels or can activate cascades that modulate channels or change gene expression

Question 15

Discuss how G protein-coupled receptors can be coupled to ion channels, and the resulting effects on membrane potential and neuronal excitability. Include examples of both “slow synaptic potentials” and “neuromodulation.”

Answer 15

Slow synaptic potentials: acetlycholine hyperpolarizes cardiac muscle by activating muscarinic receptors (open potassium channels); neuromodulation: Norepinephrine increases the number of action potentials during a depolarization by inhibiting voltage-independent calcium-dependent potassium channels

Question 16

Explain how effects of activation of different G protein-coupled receptors can interact in a cell. Compare and contrast integration of synaptic information resulting from ligand-gated vs. G protein-coupled receptors.

Answer 16

Neurotransmitters may have both convergent and divergent effects (via G protein coupled receptors); convergent: multiple transmitters, each activating its own receptor type (activate common G protein), converge on a single type of ion channel in a single cell; divergent: Multiple receptors, multiple G proteins, multiple second messengers, multiple targets for a single neurotransmitter

Question 17

Explain how diversity in the expression of voltage-dependent ion channels leads to diversity in neuronal firing patterns (e. g., adaptation).

Answer 17

Kinetics (opening and closing dynamics of channels), ion selectivity, and voltage dependence

Question 18

What are the different firing patterns of neurons?

Answer 18

stay at a stable resting potential until stimulated via EPSPs; fire repetitively with no stimulus; fire at a constant frequency during a constant depolarization; fire only briefly at the start of a constant depolarization

Question 19

Explain the role in signaling of the three functional compartments of a neuron: for receiving information, for conducting information over distance, and for transmitting information. Relate this to the anatomical structures involved (dendrites, cell body, axon, nerve terminals). Compare and contrast the structural and functional organization of motor neurons vs. somatic sensory neurons.

Answer 19

Motor neuron: dendrites and cell body receive information (spinal cord); axon conducts action potentials (peripheral nerve); nerve terminals transmit information (muscle)

Sensory neuron: sensory endings receive information (muscle); axon conduct action potentials (peripheral nerve; dorsal root ganglion (cell body) is bypassed); nerve terminals transmit information (spinal cord)

Question 20

Compare the typical positions of GABA- vs. glutamate-mediated synapses on a neuron.

Answer 20

Glutamate: axodendritc and presynaptic neuron is a projection neuron; GABA: axosomatic (or near soma) and presynaptic neuron is an interneuron

Question 21

Discuss how neurons integrate information on the millisecond time scale, using fast EPSPs and IPSPs.

Answer 21

Add EPSPs and subtract IPSPs (may also generate action potentials through voltage-gated calcium channels which effectively increase the dendrites length constant)

Question 22

Explain temporal and spatial summation of fast synaptic inputs.

Answer 22

spatial summation: As an EPSP reaches the soma, it may also combine with EPSPs arriving by other dendrites on the cell; temporal summation: occurs when EPSPs arrive rapidly in succession; when the first EPSP has not yet dissipated, a subsequent EPSP tends to add its amplitude to the residual of the preceding EPSP (dependent on time constant of neuronal membrane)

Question 23

Explain how synaptic potentials and intrinsic electrical properties of a neuron interact.

Answer 23

“Intrinsic electrical properties” = voltage-gated ion channels; these channels can either induce spontaneous neuronal firing or may modulate synaptic potentials by either increasing or decreasing the effective length constant

Question 24

Is a synaptic potential attenuated as it flows towards the soma?

Answer 24

Yes; Extended cellular processes such as dendrites behave like leaky electrical cables (capacitative and ionic currents); Dendrites tend to be long and thin. Their cytoplasm has relatively low electrical resistivity (high resistance), and their membrane has relatively high resistivity (leaky); Branching increases attenuation because current has more paths to follow; Dendrites attenuate high-frequency (i.e., rapidly changing) signals more than low-frequency or steady signals.

Question 25

Do dendrites have voltage-gated ion channels?

Answer 25

Yes; When the dendrites of Purkinje cells are stimulated strongly, they can generate large, sharp action potentials that are mediated by voltage-gated Ca 2+ channels (does not propagate down axon (action potentials are re-generated at axon initial segment through voltage-gated Na+ channels)

Question 26

What would be the expected firing pattern for a neuron with fast voltage gated sodium channels and delayed rectifier potassium channels? if another set of slower activating potassium channels is inserted into the membrane?

Answer 26

Repetitive spikes (interneuron); adaptation (some pyramidal cells)

Question 27

What is one mechanism for generating a spontaneous firing pattern?

Answer 27

Low voltage activated (LVA) T-type Ca++ channels; independent of sensory signal or transmission? (activated when a neuron hyperpolarizes)

Question 28

Why is the threshold for an action potential lower at the initial segment compared to other segments of the neuron?

Answer 28

high density of voltage-dependent sodium channels

Question 29

What are the effects of demyelination in the PNS?

Answer 29

decreased conduction velocity (lower length constant); frequency-related block (inactivation of some unmyelinated sodium channels); spontaneous activity; may excite nearby neurons (aberrantly); may stimulate remyelination (conduction velocity will still be slower since less myelin sheaths surround the site)

Question 30

Where are neurons containing serotonin located? norepinephrine? dopamine? acetylcholine? What is the importance of these neurotransmitters?

Answer 30

raphe nuclei; locus coeruleus; substantia nigra and VTA; basal forebrain complex; modulate synaptic transmission (G protein-receptor coupled)

Question 31

Which neurotransmitter is not released by calcium dependent exocytosis?

Answer 31

Nitric Oxide

Question 32

Initiation of an action potential is most distant from the cell body in which cell type?

Answer 32

Sensory neurons

Question 33

Which neurotransmitters are amino acids?

Answer 33

GABA (brain), glutamate, glycine (spinal cord)

Question 34

Which neurotransmitters are simple amines?

Answer 34

cathecolamines (dopamine, NE, E); acetylcholine, serotonin, and histamine

Question 35

What is different about secretion of dense-core secretory granules (compared to secretory vesicles?

Answer 35

storage of peptides; dense-core secretory granules are distributed randomly throughout the cytoplasm of the synaptic terminus (not organized in the active zone); act as neurotransmitters through G protein-coupled receptors (high frequency stimulation necessary); lack rapid inactivation mechanism

Question 36

The slow muscarinic EPSP is faster than the late, slow peptidergic EPSP because…?

Answer 36

the peptide can activate receptors far from the site of release

Question 37

Compare electrical synapses to chemical synapses in the CNS.

Answer 37

Electrical synapses do not amplify the signal passed from one cell to the next; they can only diminish it; lack inhibition; lack diversity in time course; lack synaptic plasticty

Question 38

Which neurotransmitter hyperpolarizes cardiac muscle by activating muscarinic receptors?

Answer 38

acetylcholine (parasympathetic innervation)

Question 39

How does Norepinephrine increase the number of action potentials during a depolarization?

Answer 39

by inhibiting voltage independent calcium dependent potassium channels

Question 40

a synaptic potential is most likely to be excitatory (an EPSP) under what condition?

Answer 40

the reversal potential is positive to threshold for an action potential

Question 41

Synaptic transmission at the neuromuscular junction and at a typical fast excitatory synapse in the brain are both what?

Answer 41

mediated by action potential-evoked calcium influx into the presynaptic nerve terminal (NMJ: about 100 quanta released; brain, 1 quanta)

Question 42

Describe the structure of an ionotropic glutamate receptor.

Answer 42

the channel appears to consist of a tetramer of four subunits; each subunit contains a large extracellular region, followed by a transmembrane segment, a loop that partially enters the membrane from the cytosolic side, and then two more transmembrane segments (loop lines the channel pore)

Question 43

GABA-mediated IPSPs are inhibitory if the reversal potential is what?

Answer 43

negative to threshold

Question 44

Describe the structure of an ionotropic GABA receptor.

Answer 44

heteropentamer; The M2 domain of each of the five subunits presumably lines the central channel pore (four transmembrane domains per subunit); selectivity for Cl − may be determined by positively charged arginines and lysines near the mouth of the pore.

Question 45

Which synaptic communication in the brain is similar to the NMJ?

Answer 45

Climbing fibers synapsing on Purkinje cells

Question 46

How does acetylcholine or NE modulate a synapse?

Answer 46

loss of adaptation; with regards to acetylcholine, this is a result of inhibition of a slow activating potassium channel

Question 47

How can acetylcholine lower heart rate? NE increase heart rate?

Answer 47

G protein-coupled receptor; opens potassium channels; modulates opening of calcium channels