Cellular Neurophysiology (NEUR0007) Notes - The Synapse

Presynaptic Mechanism
Presynaptic Mechanism
 Events leading to synaptic transmission
o Action potential invades synaptic terminal
o Ca2+ channels open
o Vesicles fuse with presynaptic membrane
o Neurotransmitter diffuses across synaptic cleft and binds receptors
o Neurotransmitter is eliminated from synapse

Brief history of theories of neuronal communication
 Purkinje neuron
o First identified cell in the nervous system
o Structure
 Large corpuscles
 Layer of granules
 Nerve fibres
 Reticular vs neurone doctrine
o Cell theory
 Biology was unified by the idea that all animals and plants were
composed of cells
o Reticular theory
 Nervous system was a large, interconnected network comprised of the fused cytoplasm of
neurons
o Neurone doctrine
 Application of the cell theory to the nervous system – neurons were separate entities
 Soup vs spark
o Spark – initially thought that all transmission in neurons was electrical
o Soup – supported theory of chemical transmission
o Is synaptic transmission mediated chemically or by direct electrical transfer of charge
o Evidence for chemical transmission at the neuromuscular junction was widely accepted by
neuropharmacologists
o Some of the physiologists thought that certain aspects were too fast to be mediated chemically
 Discovery of synaptic transmission
o Cajal’s golgi staining methods suggested the presence of contacts between cells used for
communication
 Chemical vs electrical transmission




o
 Electrical transmission
 Voltage attenuated by resistor between two neurons
 Gap junction
 Lower resistance – attenuates voltage less than electrical transmission
 Chemical transmission

,Presynaptic Mechanism
 Transmission occurs by release of transmitter binding to specialised receptors in
postsynaptic membrane
 Causes voltage change
 Why chemical?
o Gap junctions
 Same sign (usually)
 If neuron is depolarised  subsequent neuron is depolarised
 Reciprocal (usually)
 As resistance does not distinguish direction
 Fast
 Allows 2nd messengers to diffuse from one cell to another
 Time course determined by time course of events of excitation or inhibition in presynaptic
cell
o Chemical synapse
 Same sign or inverted
 Excitatory or inhibitory postsynaptic receptor
 Unidirectional
 Due to presynaptic transmitter release and postsynaptic binding
 Fast or slow
 Depends on kinetics of postsynaptic receptor
 Same signal can be decoded differently by different targets (different receptors)
 Repertoire of interactions allow complex information processing
 Evidence for chemical synapse
o Langley
 Curare blocked transmission in ciliary ganglion
 Chemical agent blocked transmission
o Eliot
 Extract from adrenal glands mimicked the action of sympathetic nerves
o Loewi
 Vagusstoff (vagus stuff) liberated from one heart slowed the next one – later identified as
ACh
o Dale and Feldberg
 ACh was released at the neuromuscular junction and sympathetic ganglion
o Eccles
 Last proponent of electrical transmission converted to chemical synapses
o Robertson
 Electron microscope first used to image ultrastucture of the synapse
 Model synapses
o Frog neuromuscular junction
 Huge synapse with lots of vesicles released from presynaptic neuron
 Lots of invagination on postsynaptic membrane
o Squid giant synapse
o Calyx of Held

Role of Ca2+ in synaptic transmission
 Extracellular Ca2+ is required for synaptic transmission

,Presynaptic Mechanism




o
 Calcium favours binding of vesicle to postsynaptic membrane
 Magnesium inhibits synaptic transmission
 Sr and Ba will partially support synaptic transmission – but release is asynchronous
 Squid giant synapse




o
 A
 Presynaptic terminal depolarised by injection of depolarising voltage step
 Inward current followed by outward current
 Block Na+ and Ca2+ channels
 Small inward current – mediated by Ca 2+ channels
 Relationship between presynaptic calcium current and transmitter release in the squid




o
 Record presynaptic and postsynaptic cell
 At increasing depolarising steps – after blocking Na and K channels = only see Ca
current
 As Ca current increases – causes release of transmitter = postsynaptic response
 More presynaptic cell is depolarised  more Ca current  bigger postsynaptic
response  until depolarise too much – as Ca channel inactivates = no more of
initial response

, Presynaptic Mechanism
 Relationship between external calcium and transmitter release in the squid




o
 Plot size of Ca current against postsynaptic response
 Increase Ca current by increasing extracellular Ca  followed by increase in size of
postsynaptic current
o Slope of Ca current is smaller than slope of postsynaptic response – suggests
co-operativity of Ca binding for transmitter release
 If 1 Ca binds  favours further binding of Ca channels

Molecular Machinery Underlying Vesicle Release
 Vesicle hypothesis of transmitter release
o Vesicle docked to presynaptic membrane  releases neurotransmitters into synaptic cleft
 Neurotransmitter release mechanisms




o
 Docking
 Vesicle first binds to presynaptic membrane
 Primed
 Vesicle ready to release
 Fusion
 Once Ca enters  vesicle fuses with membrane  releases transmitter
 Endocytosis
 Vesicle is reabsorbed in membrane  re-filed with neurotransmitter
 Key proteins of the exocytic machinery
o SNARE proteins – soluble NSF attachment protein receptors