synaptic transmission

1. synaptic transmission Basic Neuroscience NBL 120 (2007)

2. how is the signal transferred? • electrical currents in the presynaptic process induce currents in the postsynaptic process • not very efficient……….. high low

3. how do synapses work? “I vividly remember visiting him [Eccles] in his pleasant house with its fine tennis court and beautiful view over Sydney harbor.” (Katz, 1985) pharmacologists versus physiologists

4. the lawnmower incident

5. chemical transmission • a synapse is both anatomically and functionally optimized • Ca2+ • vesicles • postsynaptic receptors • central synapses are just smaller than the nmj • integration

6. nmj structure - anatomy overview axon endplate boutons mitochondria vesicles active zone 10,000 / m2 synaptic cleft basement membrane junctional fold acetylcholine receptors

7. nmj - physiology overview • stimulate motorneuron: muscle contraction • record potential change in muscle fiber • AP (high safety factor)

8. origin of the EPP • EPP: passive decay • length constant • AP: regenerative

9. PORE BINDING SITE GATE nmj - actetylcholine receptor a-bungarotoxin Bungarus multicinctus (many-banded krait) Torpedo californica (pacific electric ray)

10. acetylcholine receptor channel EPP single channel closed open non-selective cation channel

11. efficiency of the EPP • hi-fidelity synaptic transmission • design of the perfect receptor • high transmitter concentration in the cleft • rapid binding to many receptors • very fast opening (opening rate 100,000 s-1) • 99+% receptors that are bound - open • channel closes after ≈ 1 ms • agonist unbinds quickly (low affinity) • degradation and diffusion • receptor recovers without desensitization

12. mEPPs quantal hypothesis smallest evoked EPP = spontaneous mEPP “It has been suggested that the end-plate potential (epp) at a single nerve-muscle junction is built up statistically of small all-or-none units [quanta or discrete packets of transmitter] which are identical in size with the spontaneous ‘miniature epp’s’” (Del Castillo & Katz, 1954) Fatt and Katz (1952) normal EPP ≈ 200 quanta or vesicles (quantal content)

13. presynaptic mechanisms • object: • synchronous + fast release of many vesicles

14. vesicle cycling……. • synthesis of transmitter • storage of transmitter in vesicles • docking+priming of vesicles • release (fusion) of vesicles • action of transmitter on postsynaptic receptors • termination of transmitter action • recycling of vesicle membrane (endocytosis)

15. many proteins are involved….

16. delay? release….. • depolarization and Ca2+ are required

17. synaptic delay • Ca2+ channels open slowly…

18. presynaptic Ca2+ microdomains • Ca2+ is only high while channels are open presynaptic terminal Llinas et al (1995)

19. Ca2+ channels / vesicles • synaptotagmin (on vesicle): Ca2+ sensor • low affinity for Ca2+ • vesicles must be close to Ca2+ channels

20. everything is in close proximity

21. clearance of transmitter • acetycholinesterase: • 10 molecules ACh per ms (one every 100 s) • inhibition prolongs synaptic transmission….. • diffusion is very fast Katz and Miledi (1973)

22. myesthenia gravis cholinesterase inhibitor

23. CNS neurons have many synapses

24. locations of synapses axosomatic axodendritic axoaxonic dendrodendritic (e.g. inhibition) (e.g. excitation spines) (e.g. presynaptic inhibition) (e.g. reciprocal excitation)

25. coping with multiple synapses how do the multiple inputs combine to determine the output firing pattern of the neuron? dendritic integration and other mechanisms

26. central synapses • smaller (<1 m) synaptic contact • fewer active zones: • release few vesicles • failures • don’t reach AP threshold

27. inhibition versus excitation • GABA • glycine • chloride • hyperpolarizing? glutamate ACh serotonin depolarizing

28. excitatory input excitatory input inhibitory input EPSP EPSP IPSP inhibitory input threshold action potential no action potential combining excitation and inhibition

29. mechanism of inhibition • “Shunting inhibition” • Inhibitory transmitters (e.g. GABA) open Cl- permeable channels. ECl isalways more negative than AP threshold. Thus, opening up a large amount of inhibitory channels will oppose the depolarzation by any excitatory transmitter/receptor and keep the membrane close to Ecl.

30. general rule ENa +67 membrane potential (mV) • relationship between: membrane potentialion equilibrium potentials • if the membrane becomes more permeable to one ion over other ions then the membrane potential will move towards the equilibrium potential for that ion (basis of AP). RMP ECl -90 EK -98

31. action potentials closely spaced in time threshold postsynaptic action potential temporal summation action potentials separated in time threshold no postsynaptic action potential

32. threshold spatial summation membrane time constant

33. dual synaptic components….. • Wait for lecture on synaptic plasticity……

34. terminating the synaptic signal just how much glutamate is around?

35. one role of glia at CNS synapses • transmitter transporters • re-uptake • prevent excitotoxicity

36. synaptic summary • neuromuscular junction • fast synaptic transmission - highly efficient • Ca2+-dependent release of vesicles (quanta) • postsynaptic ligand-gated ion channels • synaptic integration in the CNS • synapse location • inhibition versus excitation • “shunting” inhibition • temporal versus spatial summation