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Neurobiology: Synapses and Synaptic Transmission


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sites of communication between all parts of neurons, glial cells, and blood vessels/muscles
proof that synaptic transmission is not all electrical
when Loewi added ACh to the heart muscle, he saw that it enabled the muscle to contract

(electrical activity was generated from chemical activity)
what causes an AP in the post-synaptic cell? (electrical)
current flows through gap junction channels into the post-synaptic cell and depolarizes it.

If depolarization is above threshold, voltage-gated channels open and an AP is generated.
relationship between AP on pre-synaptic cell and post-synaptic cell in electrical synapses
the signal on the pre-synaptic site must be much greater than the signal on the post-synaptic site because no amplification of the signal occurs (as in chemical synapses)
characteristics of the pre-synaptic cell in electrical synapses
1. must be large enough to contain many ion channels so a lot of current can be generated
characteristics of the post-synaptic cell in electrical synapses
must be relatively small because this means it will have a higher input resistance, which means it will undergo greater voltage change in response to pre-synaptic current.
how do electrical synapses work?
after the pre-synaptic cell is depolarized, voltage-gated channels open and current flows through them and then depolarizes the post-synaptic cell.

can be bidirectional
interneurons, characteristics
1. usually inhibitory
2. important in synchronizing activity in local cells
3. use electrical transmission because it is faster and thus can preserve precise timing of signals between distant neurons
where are electrical synapses found?
1. responsible for the tail flip of the goldfish
2. in interneurons
the amount of time between pre- and post-synaptic potentials
advantages of electrical synapses
1. latency is v. short
2. change in potential of post-syn. cell is directly related to size and shape of pre-syn. cell
3. any amount of current in the pre-syn. cell will produce current in the post-syn. cell.
4. most can transmit both depolarization and hyperpolarization
5. can coordinate large populations of neurons to act together
6. not very selective: anything can go through gap junction channels
7. bidirectional
disadvantages of electrical synapses
1. do not provide amplification (as Ca provides in chemical synapses)
how chemical synapses work
1. AP at the pre-syn. terminal causes voltage-gated Ca channels in the active zone to open, Ca rushes into the cell
2. Ca causes vesicles to fuse with the pre-syn. membrane and release NT into the synaptic cleft (exocytosis)
3. NT binds to the receptors on the post-syn. cell which opens ion channels which causes depolarization of the post-synaptic cell.
4. If this depolarization is over the threshold, an AP is produced
structure of gap junctions
2 hemichannnels exist: one on the pre- and one on the post-synaptic membrane

each hemichannel called a connexon

connexons are made up o 6 identical protein subunits called connexins.

provide low resistance
gap-junctions and decoupling cells
if there is a low cytoplasmic pH or high cytoplasmic [Ca], gap junction channels close so as not to damage other cells
ionotropic receptors
channel and receptor are same molecule

produce relatively fast synaptic actions lasting milliseconds
metabotropic receptors
channel and receptor are separate; use 2nd messengers

produce slower synaptic actions lasting seconds to minutes
where the axon of the motor neuron innervates the muscle
synaptic bouton
the end of a motor axon where it loses its myelin sheath and branches

it is here that the motor neuron releases its NT (always ACh)
neuromuscular junction
site of communication between motor neurons and muscles
4 features of the neuromuscular junction
1. pre-synaptic nerve terminal
2. synaptic cleft
3. post-synaptic compartment
4. Schwann cell compartment
basement membrane
50-100 nm wide

composed of collagen, laminins
function & location of ACh-esterases
to degrade ACh, allowing it to leave receptors on the post-synaptic cell

anchored to the basement membrane
invaginations of NMJ
contain many voltage-gated Na+ channels and ACh receptors
proteins in the NMJ
1. rapsyn
2. alpha-dystrobrevin
3. alpha/beta/gamma-syntrophin
safety factors
90% of ACh receptors of NMJ aren't used. Presumably, there are so many because without these receptors, we would die.
end-plate potential
EPSP at the NMJ
expt to study synaptic potential vs. action potential
took extracellular voltage recordings in frog NMJ in the presence of curare (which competes with ACh and prevents a post-syn. action potential)
2nd expt with frog NMJ
current was recorded at distances from the stimulation and it was found that it gets less and less the farther it moves away from the point of stimulation

receptors are highly concentrated at the NMJ compared to the rest of muscle.
what type of experiment would you use to determine which ions move through the receptors
patch-clamp expt
Ach-gated channels
generate end plate potential

allow Na+ and Ca2+ to flow in and K+ to flow out
rate limiting factor of the end plate current
the time it takes to open and close ACh-gated channels
what is a method for blocking AP in vivo?
overexpress K+ channels in muscle fiber: too many extracellular (+) charges means no AP (because ???)_
reversal potential of end plate ion channels
0mV, due to the fact that the channels are equally permeable to Na+ and K+; Na+ flows in and K+ flows out.

not selective because the pore of the channel is large
regenerativity of voltage-gated ion channels
increased depolarization due to Na+ influx causes more voltage-gated channels to open, which causes more depolarization, which causes more propagation of AP, which generates "all or nothing" APs.

positive feedback cycle
are ACh channels regnerative?


the number of ACh activated channels varies according to the amount of ACh available

the depolarization produced by Na+ flowing through these channels does not cause more ACh channels to open
what type of channel is ACh R?

structure of ACh R

1. a membrane glycoprotein
2. formed by 5 subunits: 2 alpha, beta, theta, and epsilon
where does ACh bind in the ACh R?

on the alpha subunits exposed to the membrane surface
what happens when 2 ACh's bind to the ACh R?

cause conformational change, opening the pore and allowing Na+ and K+ to flow through
which subunits of ACh R are present at birth?
2 alpha, beta, theta, and GAMMA (not epsilon)

Myasthenia Gravis
chronic autoimmune disorder that results in progressive skeletal muscle weakness

causes rapid fatigue and loss of strength

eye muscles particularly affected
2 forms of Myasthenia Gravis
1. congenital: caused by deficiency of ACh at the end plate

2. autoimmune: characterized by the presence of antibodies that react with ACh R --> interferes with synaptic transmission --> reduces # of ACh R --> muscles become weak
general function of rapsyn
important for synapse clustering
muscle-specific tyrosine kinase
synaptic integration
mechanism by which neurons integrate thousands of synaptic inputs to trigger an AP

input both inhibitory and excitatory
NMJ vs. CNS: how many innervations?
NMJ: one muscle fiber receives input from one axon

CNS: neurons can receive input from many axons of different neurons
NMJ vs. CNS: does each AP trigger an AP in the post-synaptic cell?
NMJ: yes

CNS: rarely the case because MUCH excitatory input is needed for an AP to fire (each synapse only produces about 1 mV and about 70 mV are needed)
NMJ vs. CNS: size of synaptic cleft
NMJ: large

CNS: small
NMJ vs. CNS: types of NT

CNS: many--GABA, glutamate
NMJ vs. CNS: type of receptors
NMJ: ionotropic

CNS: both ionotropic and metabotropic
NMJ vs. CNS: excitatory, inhibitory synapses
NMJ: all synapses excitatory

CNS: both excitatory and inhibitory synapses
why were spinal motor neurons used to study synaptic integration?
they're large, easily accesible, and have both inhibitory and excitatory synapses
excitatory and inhibitory synaptic connections mediating stretch reflex
see figure 12.1

interneuron makes excitatory connection with extensor motor neuron and an inhibitory connection with the flexor motor neuron

quads are stimulated, hamstrings relaxed
idealized experimental setup for studying excitatory synapses
the whole afferent nerve from the quads can be stimulated electrically with extracellular electrodes

OR single axons can be stimulated with an intracellular current-passing electrode inserted into the neuron cell body

AP stimulated in the afferent neuron from quads stimulates an EPSP in the extensor motor neuron
idealized experimental setup for studying inhibitory synapses
inhibitory interneurons receiving input from quad pathway are stimulated intracellularly

an AP generated in the inhibitory neuron in the extensor pathway causes an inhibitory PSP in the flexor motor neuron
magnitude of EPSPs in the CNS
up to 1 mV; usually .2-.5 mV

(thus many are needed to generate an AP)
the ability of inhibitory synapses to shape the pattern of firing in a cell

sculpturing results in a distinctive pattern of firing of impulses
Type I synapses
glutamatergic (excitatory)

on dendrite

wide synaptic cleft, dense pre-syn. region

round synaptic vesicles
Type II synapses
GABA-ergic (inhibitory)

often contact cell body

narrow synaptic cleft, less obvious pre-syn. region

flat synaptic vesicles
the major excitatory NT in the brain and spinal cord

mediated by both ionotropic and metabotropic receptors
types of ionotropic receptors (acted upon by glutamate)
always excitatory

AMPA receptors, kainate receptors, NMDA receptors
metabotropic receptor (acted upon by glutamate)
ACPD (both inhibitory and excitatory)
drug that selectively blocks NMDA receptors
drug that selectively blocks non-NMDA receptors
early component of EPSP
generated by non-NMDA receptors

receptors gate cation channels with relatively low conductances that are permeable to both Na+ and K+, but not Ca2+
late component of EPSP
generated by NMDA receptors
expt that separates early component from late component (EPSP)
voltage clamp with APV on hippocampus neurons: late component disappears when treated with APV. Thus, the early component is due to non-NMDA, late component due to NMDA (which APV blocks)

-80mV: no difference btwn APV and non-APV because NMDA is blocked by Mg2+.
-40mV: small late current in non-APV
+20mV: prominant late outward current in non-APV
how Mg2+ is expelled from NMDA receptors
1. glutamate is released and binds to AMPA receptors
2. Na+ enters the cell via the receptors
3. this depolarization causes Mg2+ to be expelled from the NMDA receptor due to electrostatic repulsion (depolarization)
features of AMPA receptors
not permeable to Ca2+, early component of EPSP, low conductance
features of NMDA receptors
high conductance, requires depolarization + glutamate + glycine (cofactor), permeable to Na+, K+ and Ca2+
NMDA receptors and drugs
PCP blocks NMDA receptors so that Ca2+ cannot enter the cell

schizophrenia is similar
Ca2+'s relation to NMDA receptors
NMDA receptors let Ca2+ into the post-syn. cell, and it is responsible for carrying much of the current

Ca2+ activates other enzymes, acts as 2nd msgr.
main inhibitory NT in brain and spinal cord
expt to show how inhibitory signals work
systematically changed the level of the resting membrane potential while stimulating an inhibitory pre-syn. neuron to fire an AP. At resting potential (-65mV), a small hyperpolarizing potential was generated when the interneuron was stimulated. At -70mV, no change in potential was recorded. At potentials more neg. than -70, a depolarizing response was discovered in the motor neuron.
what do IPSP's result from (ion)?
an increase in conductance to Cl- (more Cl- influx)
axon hillock
contains a large amount of Na+ channels with a lower threshold than soma/dendrite

the decision whether to fire an AP or not is made here
temporal summation
consecutive synaptic potentials at the same site are added together in the post-syn. membrane

determined by time course of EPSP and frequency

the larger the time constant, the greater the ability for temporal summation
spatial summation
integration from many neurons acting on different parts of the post-synaptic membrane

depends on length constant (the larger the length constant, the more likely neurons are to be brought to threshold from 2 different inputs)
axo-somatic synapses
axon to cell body

often inhibitory (sculpturing): the depolarization from an excitatory current must move through the cell body before it is propagated in the axon
dendro-somatic synapses
dendrite to cell body

often inhibitory
axo-dendritic & dendro-dendritic synapses
often excitatory
axo-axonic synapses
neither inhibitory or excitatory

modulatory synapses (e.g., controls amount of NT release)
expt to determine if Na+ is involved in NT release
inserted recording electrodes into the pre- and post-synaptic cells and blocked Na+ channels with TTX. AP still resulted, meaning it did not stop NT release.

when they blocked Na+ channels for 30+ minutes, they found that no AP resulted any more because the pre-synaptic potential was extinguished.
expt to prove K+ is not involved in NT release
add 2 electrodes to pre-syn. cell (one recording, one stimulating) and one to the post-syn cell.

add TEA: NT release still occurs, although depolarization is constant since K+ cannot flow into the cell and repolarize it-->transmitter release is sustained
expt to test Ca2+ involvement in NT release
found that if extracellular [Ca2+] is increased, there is an increase in the post-syn. potential. If extracellular [Ca2+] is decreased, there is a decrease in post-syn. potential

implied Ca2+ flows into the cell

the amount of Ca2+ current through voltage-gated channels determines amount of NT release, which in turn determines magnitude of post-syn. potentials
abundance of Ca2+ channels at presyn. terminal
found that there are many Ca2+ channels here, which both depolarize and act as second messengers
Ca2+ concentration in active zone
in the active zone during the AP, Ca2+ reaches a concentration of 100mM
latency in EPSP
due to the fact that it takes time for NT to bind to the post-synaptic cell.

First you see the pre-syn. AP (due to Na+ and K+), then the inward current of Ca2+, then the EPSP, then the AP in the post-syn. cell if the EPSP was above threshold
evoked release
stimulated NT release; seen as multiples of the unit potential
quantized release of NT
produces a post-synaptic potential of fixed size
expt to determine if NT release is quantized
used frog NMJ and TTX
miniature end plate potentials
small, spontaneous post-synaptic potentials of about .5mV.

largest at site of nerve muscle contact and decay electronically with distance.

frequency increased by depolarizing the pre-synaptic terminal
Ca2+ and quantized NT release
alterations in external Ca2+ concentration do not affect the size of a quantum of transmitter, but the average number of quanta released in response to a pre-synaptic AP.

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