NeuroSciense 2

The chemical and electrical processes by which the information encoded by action potentials is passed on at synaptic contacts to a target cell is called synaptic transmission. 

Chemical synapses is the most abundant type of synapse in the nervous system. 

Cytoplasmatic continuum 

Gap Junction

Gap junction channels 

No cytoplasmatic continuum 

Synaptic vesicles 

Synaptic vesicle fusing 

Postsynaptic neurotransmitter receptor

In 1903 Otto Loewi wondered why one of the heart nerves (the accelerator) speeds up the heart and the other (the vagus) slows it down, even though the electrical pulses of the nerves were nearly identical. 

Loewi suggested that the two nerves released different chemicals at their terminals when stimulated. The vagus chemical would slow down the heart and the accelerator chemical would speed it up. 

Hearts, with their nerves intact, were dissected from two frogs. 

The hearts were hooked up to mechanical devices which recorded their heart beats. 

Then the vagus nerve of one heart (the donor) was electrically stimulated. 

The donor heart immediately slowed down, as expected. 

A sample of the fluid passing through the donor heart was taken with a small pipette and this fluid was dripped onto the second heart (the recipient). 

The recipient heart slowed down, even though its vagus had not been stimulated. Chemicals released by the donor heart into the fluid were sufficient to produce slowing.

End plate potentials (EPPs) are the depolarizations of skeletal muscle fibers caused by neurotransmitters binding to the postsynaptic membrane in the neuromuscular junction.

They are called "end plates" because the postsynaptic terminals of muscle fibers have a large, saucer-like appearance.

When an action potential reaches the axon terminal of a motor neuron, vesicles carrying neurotransmitters (mostly acetylcholine) are exocytosed and the contents are released into the neuromuscular junction. These neurotransmitters bind to receptors on the postsynaptic membrane and lead to its depolarization. In the absence of an action potential, acetylcholine vesicles spontaneously leak into the neuromuscular junction and cause very small depolarizations in the postsynaptic membrane. This small response (~0.5mV) is called a miniature end plate potential (MEPP) and is generated by one acetylcholine containing vesicle. It represents the smallest possible depolarization which can be induced in a muscle.

An action potential in the presynaptic motorneuron can cause a transient depolarization of the post synaptic muscle fiber. This change in membrane potential, called an end plate potential (EPP) is normally large enough to bring the membrane potential of the muscle cell well above the threshold for producing a postsynaptic action potential. The post synaptic action potential triggered by the EPP causes the muscle fiber to contract. 

Sir Bernard Katz 

The break through of katz's experiment: spontaneous changes in muscle cell membrane potential occur even in the absence of stimulation of the presynaptic motor neuron. These changes have the same shape as EPPs but are much smaller. 

Release of acetylcholine does occur in discrete packets, each equivalent to a MEEP. 

Smallest EPP not smaller than a mini. 

Increments in amplitude occurs in units or "quanta" 

One quanta is the smallest unit of transmitter release. 

The increments have the size of a mini. 

One miniature EPP correspond to the release of one vesicle.

AP synchronize vesicular release.

P_x= [n! /(n-x)!x!] * [p^xq^n-x]:

n: number of release sites (only one vesicle (quantum) can be released for each release site)

p: probability of releasing one vesicle (assumed to be the same at each release site)

q = 1-p ; i.e. the probability of not releasing a vesicle

P_x: probability of releasing x vesicles

Transmitter release can be described with binomial statistics. For large n and low p (e.g. low external [Ca2+]) transmitter release can be described by a Poisson distribution:

P_x = (mx^e-m) / x!

m = p*n ; i.e. average number of quanta released over all trials

The classic three-pool model. 

1. The reserve pool makes up ~80-90% of the total pool

2. The recycling pool is significantly smaller (~10-15%). 

3. The readily releasable pool (RRP) consists of a few vesicles. 

Kiss and Run 

Full fusion 

• Exocytosis 
• Endosome --> Budding --> Docking --> 

•                                    Endocytosis
• Priming --> Fusion --> Budding --> Endosome

Highly nonlinear relationship: EPP = k[Ca²⁺]⁴

When the action potential arrives at the synaptic terminal, the resulting depolarization results in the activation of voltage-gated Ca2+ channels.

Ca²⁺ enters the terminal, according to its electrochemical gradient. The amount of Ca2+ that enters the terminal is extremely dependent upon the amplitude and shape of the action potential. Short duration APs spend less time above the voltage threshold for activation of voltage-gated Ca²⁺ channels, resulting in the opening of fewer channels, and less Ca²⁺ entry. 

Ca²⁺ entry triggers a conformational change in specific proteins in docked synaptic vesicles that results in fusion of the vesicle to the plasma membrane. 

Vesicle fusion causes the neurotransmitters contained in the vesicle to spill out into the synaptic cleft, where they can diffuse toward the receptors on the postsynaptic cell.

At the synapse, vesicle fusion is a tightly regulated process, compared with the constitutively active membrane-recycling processes that are involved in protein trafficking through the endoplasmic reticulum/Golgi apparatus or cell division.

Compared with the other steps occurring at a chemical synapse, vesicle fusion is extremely fast.

ωconotoxin MVII A :Blocks N-type Ca2⁺ channels

ω Agatoxin IVa: Blocks P-type Ca²⁺ channels

Channel name:  CaV2.2

Conductance: 20pS

Activation Va = +7.8mV

Blockers: conotoxin GVIA

Channel distribution: neurones (presynaptic terminals, dendrites, cell bodies)

Channel name: CaV2.1

Conductance: 9, 14, 19pS

Gating inhibitors: -agatoxin IVA

Channel distribution: neurones (presynaptic terminals, dendrites, some cell bodies)

Acetylcholine + water--> Choline + Acetate 

The enzyme used is Acetylcholinesterase

Physostigmine (eserine)

Nerve Gas (Sarin)

Present in Presynaptic Neuron Activity

Dependent Release

Postsynaptic Receptors for Neurotransmitter

Docking

• The SNAREs: Syntaxin
•                  : synaptobrevin 
•                  : SNAP-25

High stabilization energy of the bundle;3-17 complexes. Sufficient energy for fusion

Synaptotagmin: a Ca²⁺ binding vesicular protein