This document was created by Alex Yartsev ([email protected]); if I have used your data or images and forgot to reference you, please email me. Transmission at the and the First, an orgy of nomenclature - Inhibition can be POST-SYNAPTIC or PRE-SYNAPTIC - DIRECT inhibition: inhibition after an inhibitory postsynaptic potential- “direct” because it is inhibition by virtue of being hyperpolarized by an arriving inhibitory stimulus, not because of any previous discharges of the post—synaptic cell - INDIRECT inhibition is the result of previous postsynaptic neuron discharges, eg. when the postsynaptic cell is refractory to excitation because it just fired - PRESYNAPTIC INHIBITION AND FACILITATION happens when an inhibitory neuron sends a nerve ending to an excitatory synapse on another neuron, and the two nerve endings form an axoaxonal synapse. o There are 3 mechanisms of presynaptic inhibition: . Activation of chloride channels in the PRE-synaptic neuron – that hyperpolarizes the excitatory nerve ending and thus reduced the magnitude of excitatory ; and that in turn reduces the amount of that enters the excitatory nerve ending, reducing the amount of excitatory released . Voltage-gated potassium channels can open, thus hyperpolarizing the membrane by allowing a stream of potassium to exit, and thusa decreasing the inward calcium stream upon the arrival of the action potential . Direct inhibition of neurotransmitter release independent of calcium influx

- GABA is a model presynaptic inhibitory neurotransmitter o GABAA receptors are Chloride channels o GABAB receptors are Potassium channels

Pre-synaptic facilitation also occurs andusually features a prolongation of the action potential, and INCREASED calcium release into the cell (thus increased release of neurotransmitter) o for example: acts a presynaptic facilitator; it increases cAMP activity, which results in phosphorylation of potassium channels (which become closed in the phosphorylated state). The result is delayed repolarization, and thus a prolonged action potential.

ORGANISATION OF INHIBITORY CIRCUITS A typical RENSHAW CELL: inhibitory interneuron of the spinal cord

The Renshaw cell receives input from a collateral axon of a spinal motor neuron; it then sends a post-synaptic inhibitory signal to both the same neuron that stimulated it ( thus exerting a negative feedback) as well as a neighboring neuron

SUMMATION AND OCCLUSION - SUBLIMINAL FRINGE: if neurons A and B both receive an excitatory input from the same network of endings, and A reaches firing threshold by spatial summation (it has more excitatory endings contacfting it) then B, which is excited but not yet at threshold, is said to be in the SUBLIMINAL FRINGE of neuron A - Neurons are said to be in the subliminal fringe if they are affected by excitatory input, but not brought to firing thereshold ( the “discharge zone”) - OCCLUSION is the result of presynaptic endings sharing postsynaptic neurons. There is a decrease in expected response from any given single stimulation

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THE NEUROMUSSCULAR JUNCTION - An axon of a motor neuron loses its myelin as it approaches a muscle fiber Action - It divides into several terminal boutons, or Potential “endfeet”, which contain - The endfeet fit into folds of the thickened MOTOR END PLATE which is the part of the muscle fiber - Only one fiber ends at one end plate; there is no convergence of input - When an action potential arrives, ity triggers voltage gated calcium channels - These channels activate the protein machinery (SNAPs , synaptosomal nerve associated proteins, and VAMPs, vesicle- associated membrane proteins) which drags the vesicles to the surface of the synapse - The vesicles release acetylcholine - The acetylcholine binds to the postsynaptic acetylcholine receptor - The receptor becomes conductive to Na+ and K+ - The current sink created by this brings the Voltage- gated Ca++ adjacent membrane to firing level channel - The acetylcholine is rapidly degraded by acetylcholinestrase

Nicotinic Acetylcholine receptor

END PLATE POTENTIAL - The end plate contains about 15-40 million Ach receptors - Each nerve impulse releases about 60 vesicles - Each vesicle contains about 10,000 molecules of Ach - This amount is about 10 times what you actually need to reach a full end plate potential

QUANTAL RELEASE OF NEUROTRANSMITTER - The synapse RANDOMLY releases Ach at rest. - This produces minute depolarizing spikes, each about 0.5 mV - The size of the quanta varies DIRECTLY with the Ca++ concentration and INVERSELY with Mg++ concentration - Something very similar seems to happen at all synaptic junctions

MYASTHENIA GRAVIS: antibodies to the acetylcholine receptor LAMBERT-EATON SYNDROME: antibodies to the voltage-gated calcium channel

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NERVE ENDINGS AT SMOOTH MUSCLE - Postganglionic neurons branch extensively over the surface of smooth muscle fibres - There are NO END PLATES - Some of the endings contain acetylcholine vesicles, other endings contain noradrenaline - There are vesicle-containing VARICOSITIES along the axons of these nerves; the neurotransmitter seems to be released from these along the whole axon - Thus, one neuron innervates many effector cells - This is called synapse en passant- “synapse in passing” NERVE ENDINGS AT - Cholinergic and adrenergic fibres innervate the sinoatrial node, atrioventricular node and the bundle of His. - Noradrenergic fibers also pass into the ventricular muscle - In the ventricle, the contacts between the noradrenergic fibers and the muscle are en passant JUNCTIONAL POTENTIALS - The smooth muscles receive noradrenergic and cholinergic nerve endings; in some muscle the cholinergic is excitatory and the noardrenegic are inhibitory; in other tissues its vice versa. - The excitatory neurotransmitter, when released, produces a small discrete partial - looks like a small end plate potential. These are called excitatory junction potentials. - Similarly, the inhibitory neurotransmitter produces inhibitory junction potentials - These potentials are summative and can bring the cell to threshold - The potentials spread electrotonically.

DENERVATION HYPERSENSITIVITY - IT IS WELL KNOWN: If you severe a nerve supply to a muscle, it becomes abnormally sensitive to acetylcholine. - The denervated skeletal muscle will also atrophy. - Smooth muscle does NOT atrophy, but does become abnormally sensitive - This is due to increased synthesis of neurotransmitter receptors. - The upregulation of receptor synthesis is due to the decreased neurotransmitter release - Hypersensitivity is limited to the structures immediately innervated by the severed neuron

References: Ganong Review of Medical physiology, 23rd ed, chapter 6