1. Cellular Neuroscience (207) Ian Parker Lecture #13 – Postsynaptic excitation and inhibition

2. Postsynaptic excitation and inhibition EXCITATION – current flow through neurotransmitter-activated channels that tends to depolarize the cell beyond (more positive than) the threshold for trigering an action potential INHIBITION – current flow through channels that tends to stop action potentials from firing by preventing the membrane potential exceeding the action potential threshold. (Does not necessarily imply hyperpolarization) Whether a given synapse is excitatory or inhibitory depends on the ionic selectivity of the postsynaptic channels. A particular neurotransmitter is not inherently excitatory or inhibitory – though it is often the case that a given neurotransmitter consistently plays a given role; e.g. glutamate as an excitatory transmiiter and GABA as an inhibitory transmitter. But, some transmitters (e.g. ACh) can be excitatory or inhibitory, depending on the synapse.

3. Ionic basis of the endplate potential Voltage clamp the endplate. Record currents (e.p.c.’s) evoked by nerve stimulation (ACh) at different holding potentials Plot I/V relationship of e.p.c.’s. Reversal potential ~ -10 mV: i.e. not corresponding to the Nernst potential for any single ion. Reversal potential changes if [Na] or [K] in extracellular solution are changed, but not with changes in [Cl] or [Ca]. So, endplate channels are permeable to both Na and K

4. Equivalent electrical circuit of a nicotinic Ach channel (endplate channel)

5. Equivalent electrical circuit for ACh action on the endplate Summated conductance of many thousands (how many??) of nAChR channels

6. Relationships between time courses of channel openings, e.p.c. (endplate current) and e.p.p. (endplate potential) e.p.c. kinetics are determined by mean channel open time e.p.p.kinetics are determined by membrane RC time constant

7. Effects of cholinesterase inhibition ACh-esterase in the synaptic cleft hydrolyzes ACh to choline (which is recycled into the nerve terrminal) This breakdown is very rapid, so that each ACh molecule gets only one chance to bind to a receptor site before it is hydrolyzed. But: if esterase is blocked (e.g. with neostigmine), an ACh molecule can bind repeatedly and open several channels before eventually diffusing away. Peak amplitude of e.p.c. is not changed, but its decay is slowed. Thus e.p.p. becomes larger (integral of charge movement during e.p.c) Used for treatment of myasthenia gravis: autoimmune disease of impaired nerve/ muscle transmission owing to antibodies against AChR.

8. Integration of excitatory signals by a neuron (The nerve-muscle junction does not process information, just one-to-one transmission) 1. TEMPORAL SUMMATION The e.p.s.p. (excitatory postsynaptic potential) produced by a single presynaptic action potential may not be enough to depolarize the postsynaptic neuron to threshold for an action potential. BUT, if stimulated several times in quick succession e.p.s.p.s summate to depolarize above threshold. (Temporal summation via RC time constant of membrane.)

9. 2. SPATIAL SUMMATION Summation of (near) simultaneousexcitatory conductances from several synapses to give an e.p.s.p. large enough to exceed action potential threshold. Spatially limited by cable properties (length constant) of dendrite.

10. Inhibitory conductance changes Receptors to GABA and glycine cause opening of Cl-permeable channels Equilibrium potential for Cl - in neurons is around -80 mV. So action of GABA is to “pull’ the neuron’s potential toward -80 mV. This might cause a hyperpolarization or depolarization, depending on the initial resting potential. So – if GABA actually causes a depolarization, why is it inhibitory?

11. 1.The potential change evoked by GABA cannot go more positive than -80 mV no matter how much GABA : This is well below the action potential threshold 2.Current through GABA-activated channels tends to hold the neuron at -80 mV, opposing depolarization by excitatory synapses. Of course, interactions between inhibitory and excitatory synapses depend on both temporal and spatial integration, as with interactions between excitatory synapses.

12. Equivalent circuit for interactions between excitatory and inhibitory synapses