Neurophysiology for Neuroanatomists: Excitability Flashcards
What things occur during a monosynaptic or myotatic stretch reflex?
manual stretching with elicitation of a reflex leads to transduction (converison of one form of energy to another) of spinde stretch into a graded electrical signal (receptor potential) which in turns lead to attaining threshold for an actiion potentioal in the peripheral process of a sensory neuron (the cell body is in the dorsal root ganglion).
The AP propagates into the dorsal root of the spina cord and depolarizes the membrane at synapses on an alpha motorneuron in the spinal cord ventral horn
What happens after the AP propagates into the dorsal root of the spina cord and depolarizes the membrane at synapses on an alpha motorneuron in the spinal cord ventral horn?
At this pt, another transduction step occurs where an electrical event (AP) results in release of a chemical transmitter from the DRG neuron, which diffuses across the synpatic cleft and binds to postsynaptic receptors, generating a graded postsynaptic potential (PSPs) which integrates with other PSPs and may result in an AP in the motoneuron.
This AP propagates along the motoneuron axon and invades the synaptic terminal at the NMJ, causing depolarization, and opening of voltage-gated Ca2+ channels, causing Ach release which binds to nicotinic receptors
One motoneuron innervates many muscle fibers.
The resultant endplate potentials elicit APs in all of the muscle fibers innervates by that motoneuron, causing muscle contraction
Describe the Fluid Mosaic model of cell membranes
the membrane is a lipid bilayer with embedded proteins. The proteins can be fixed or mobile in the membrane.
How are membrane pores likely regulated?
by movement of part of the channel in response to a gating stimulus (e.g. voltage, ligand bindings, temp, etc.)
The ______ is the part of the membrane channels which determines which ion types can move through the channel
selectivity filter
Current is movement of charge. In an electrical wire this charge is carried by electrons. In biological systems, charge is carried by movement of ions. A resistor is a circuit element that resists the flow of charge. Ion channels act like variable resistors. Conductance is the reciprocal of resistance. Ohm’s law: V=I*R
A capacitor is a circuit element that can store charge. In an electronic circuit, capacitors are two paltes that are good conductors of electricity, with an insulating substance between them. When connected to a voltage source, charge is stored on the plates; “+” charges on one plate and “-“ charges on the other. The larger the plate, the more charge they can store. The thinner the insulation between plates, the greater the charge storage.
A cell membrane is two conductive plates that is very thin. Thus, the structure of the memrbane gives it properties of a capacitor: that is, membranes are good at storing charge
T or F. Membranes are semi-permeable to ions
T. That is, the membrane is permeable to some iosn and not others.
At rest, membranes are permeable to primarily what?
K+. This selectiveness results in seperation of charge which results in a transmembrane voltage
The conc of the principle ion species are different intra- and extracellularly. Howis this maintained?
NaKATPase (K+ high in the cell and Na+ high outside the cell)
NOTE: Cl- ions mostly passively distribute across the membrane
What is the typical resting membrane potential?
~ -70 mV
What ar the typical conc gradients of ions in mammalian neurons?
ENa= +50 mV
EK= -100 mV
ECl= -60 mV
The resitng membrane potential depends on all of these and is determined via the Nernst Eqn
NOTE: If the membrane is at equilibirum and only permeable to a single ion speces, membrane potential is described by the Nernst Eqn
In practice, the eqn is used to predict what ion species is dominating membrane permeability under a given set of circumstances
The _______ eqn preicts the membrane potential at equilbrium when all permeant ion species are accounted for
Goldman-Hodgkin-Katz eqn
T or F. In real life, the membrane potential is not typically at equilibirum, but rather ion conc ratios are actively maintained using a NaKATPase
T. 3 Na+ out; 2K+ in. (it is thus electrogenic, i.e. contributes to the membrane potential). Similarly, a Ca-ATPase transports Ca2+ ions across the cell membrane
T or F. Not all membrane in a cell is isopotential at a given time
T. Due to complicated geometry. Rather, signals propagate through the neuron and the passive RC properties of membrane set biophysical limits on this propagation of electrical signals
Describe electrotonic (passive) signal propagation
Voltge is maximal at the pt of stimulation and the amplitude of the signal decays exponentially with distance from that pt. Note that this decay is symmetric and bidirectional in a uniform axon
What is the ‘time constant’?
the time for an electrical neuronal signal to decay to 1/e of the maximum amplitude. It is longer for larger diameter cables b/c there is a greater cross-sertional area for charged to move along relative to surface area (leakage across the memrbane is proportional to sruface area)
Signal propagation speed is also lost with increasing distance along an axon (in addition to amplitude). WHy?
due to charging the membrane capacitance
T or F. At rest, the cell membrane potentail is polarized
T. The inside is negatively charged relative to the outside (-70 mV)
Events which enhance membrane potential (i.e. make it more negative) are called what?
hyperpolarizing (opposite= depolarizing)
What does the term threshold mean?
it is the voltage at which inward (depolarizing) current is balanced y outward (hyperpolarizing) current. Any further depolarizaiton leads to the all-or-none AP response
The falling phase of an AP is also called ______
repolarization
During an AP, the membrane potential “overshoots” OmV to +30 mV. What is the significance?
Complete loss of the selectivity of the membrane for ions would be expected to result in the membrane potential reaching 0mV (but not beyond). The fact that 0mV is overshot suggests that selectivity is maintained but that K+ no longer dominates.
Upon repolarization, membrane potential undershoots the original resting potential. This is aka _______
afterhyperpolarization (AHP)
What are two major types of neural electrical signals?
graded potentials and action potentials (APs)
Describe graded potentials
these are passive responses (as predicted by an RC circuit). The amplitude of the response is proportional to the amplitude of the stimulus (linear relationship as predicted by Ohm’s Law)
What are some exs of graded potentials?
receptor potentials (due to stimultation of a snsory receptor)synaptic potentials (due to synaptic transmission)
Describe action potentials
These are active responses (voltage-dependent). There is a threshold, above which the amplitude of the response is sterotypes (all-or-none), large, and typically brief
What causes the uptstroke in an AP?
increase in membrane permeability to Na+
What causes the downtstroke in an AP?
inactivation of Na+ channels as well as activation of voltage-gated K+ channels (also caused the undershoot)
What are the three main states of membrane channels?
closed, activated (open), and inactivated
When are Na+ channels closed?
more negative than -60mV (note that nearly all Na+ channels will be open by 0mV)
Continued depolarization causes open channels to do what?
enter a third state, the inactivated state.
How are inactivation and deactivation different?
Inactivation is the process of going into the inactivated state from either open (more common) or closed. In this state, no ions are conducted through the channel and the channel is not available to be activated by another depolarization, while in the deactivated state, the channel is closed by may be opened due to depolarization
What is required to remove inactivations (i.e. transition from an inactivated state to a closed state)?
a finite time at a negative membrane potential (e.g. resting potential or more negative)
Only after channels are back in the closed state are they once again available to be activated
T or F. For the repolarizing K+ channel, there is no inactivation over time scales relevant for an AP
T. Thus it only has two states: closed or open (activated)
Describe repolarizing K+ channels
At resting potential, most are closed. Upon depolarization, more of the K+ channels open. This process is slower than in Na+ channels and occurs at relatively more depolarized potentials than Na+ channels
Repolarization eventually causes channel closure
After eliciting an AP, there is typically a time period over which is requires a larger second stimulus to elicit another AP. What is this time called?
relative refractory period
What causes the relative refractory period?
due to increased K+ permeability (that also causes the AHP) following the AP
What causes the briefer Absolute refractory period during which no stimulus, no matter how large, can elicit an AP?
too many Na+ channels being in the inactivated state
Action potentials are more efficiency than graded (electrotonic or passive) potentials are propagating signals over long distances. Why?
It is regenerated in each patch of membrane that reaches threshold (thus, will remain at the same amplitude)
How does AP propagation occur?
At each patch of membrane that is depolarizes beyond threshold, an AP is generated, which propagates to the adjacent patch of membrane, typically a short distance. Note that if the stimulus occurs in the middle of a cable (e.g. axon), propagation would be bidirectional from that pt. In real neurons, APs typically initiate at one point (generally the axon initial segment or the first Node of Ranvier) and propagate along the axon as well as back into the soma and dendritic tree
Within the axon, propagation is usually unidirectional due to Na+ inactivation and the resulting refractory period.
What things increase the conduction velocity of an AP along an axon?
increasing diameter of the axon (more charge carriers vs. surface area)
myelination via Schwann cells in the periphery and oligodendrocytes in the CNS
Myelin sheaths are interrupted by unmyelinated membrane areas known as what?
Nodes of Ranvier
How does myelination work?
Myelin, a lipid, is wrapped around the axon, serving to increase the resistance of the membrane for ions (since ions cant pass through lipid). AND the increased thickness decreases the ability of the membrane to act as a capacitor. Decreased capacitance= less charge stored on the membrane and more propagates.
All of this increases the conduction velocity
T or F. Movement of charge between Nodes of Ranvier is passive (electrotonic)
T.
Note that while the amplitude of APs DOES decrease along the myelinated areas of the axon while it passively moves to the next one, typically threshold is met at the next NOR due to the high amplitude and relatively short distance between them
T or F. Amplitude of signal is maintained by increaseing the resistance of the membrane (to leakage) and decreasing the capacitance
T.
What are the fastest conducting axons in the body?
Group 1 afferents and alpha motneuron axons
In mammalian myelinated axons, what is most important for repolarization of APs?
Na+ channel INactivation more than K+ channel activation
In neurons, the typical spike (AP) initiation zone is what?
either the axon initial segent or the first Node of Ranvier (thought to be due to a combo of hgih Na+ channel density and geometric factors)
What happens in MS?
demyelination of some axons due to inflammation
What are channelopathies?
mutations in AP channels which alter function and lead to pathology
What is the structure of voltage-gated AP Na+ channel?
alpha subunit with a 4 domain AA sequence, each consisting of 6 transmembrane spanning regions and arranged so as to form the aqueous pore between them (mutated in channelopathies)
and auxilliary subunits
Point mutations to the Na+ alpha subunit can lead to disease, including _____
generalized epilepsy with febrile seizures (GEFS) syndrome, marked by slowed inactivation of Na+ channels
Myotonia and periodic paralysis are caused by Na+ channel mutations in skeletal muscle
Mutations in particular types of Ca2+ channels can also lead to channelopathies. Namely:
Familial hemiplegic migraine
Episodic ataxis type 2
CSNB
Lambert-Eaton syndrome
Describe Familial hemiplegic migraine
caused by mutation of P/Q type Ca2+ channels (Channel name: CaV2:2; gene name= CACNA1A)
What causes episodic ataxia type 2?
truncation mutants of Cav2.2 Ca2+ channels
What causes CSNB?
truncated L-type Ca2+ channels (CaV1.4) in the retina (alters sensitivity of the channels to modulation by calmodulin)
What happens in Lambert-Eaton syndrome?
small cell carcinomas produce Abs to P/Q type Ca2+ channels at NMJs
Myotonia (hyperexcitability of muscle) can be caused by mutations in what?
voltage-gated Cl- channels
NOTE: Unlike neurons, skeletal muscle has considerable Cl- permeability at rest (Cl- contributes to the resting potential), resulting in a very negative resting potential (~-90mV). In myotonia, the resting potential of muscle fibers becomes relateively depolarized, making them more excitable
The most prevalant known cause of BFNE (Benign familial neonatal seizures) is what?
mutation of KCNQ2, a gene encoding a voltage-gated K+ channel
What underlies the cause of Episodic ataxia Type 1?
mutations in Kv1.1-type K+ channels in Purkinje cells
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A. GABA binds to a ligand gated anion channel
Depolarization usually occurs by positive charge going in or Cl- leaving the cell. In adults, Cl- enters the cell when you open a GABA channel (with valine or whiskey for example) to hyperpolarize the cell. But in infants the Cl- content in the cell is higher, and Cl- leaves when the GABA channel is open and the cell depolarizes to promote seizure
