Nens220, Lecture 6 Interneuronal communication John Huguenard

Electrochemical signaling

Synaptic Mechanisms Ca 2+ dependent release of neurotransmitter –Normally dependent on AP invasion of synaptic terminal Probabilistic

Probabilistic release Synaptic release is unreliable –Action potential invasion does not necessary evoke release –Net response is product of number of terminals (or release sites, n ), size of unitary response (q), and probability (p) of release at each terminal –N varies between 1 and 100 –p between 0 and 1 –q is typically on the order of 0.1 to 1 nS

Binomial probability

Postsynaptic properties: ionotropic receptors Ligand gated receptors Directly gated by neurotransmitter – ion pores Can be modeled analogously to voltage-gated channels

The probability of a ligand gated channel be open (P s ) will depend on: on and off rates for the channel With the on rate dependent on neurotransmitter concentration This can be approximated by a brief (e.g. 1ms) increase, followed by an instantaneous return to baseline

Three major classes of ligand gated conductances: ligands Excitatory –Glutamate AMPA/Kainate receptors (fast) NMDA receptors (slow) Inhibitory –Gamma amino butyric acid GABA A receptors

AMPA (glutamate) Fast EPSP signaling  rise < 1ms  decay : ms Cation dependent E AMPA 0 mV.

Ca 2+ permeability: AMPAR Depends on molecular composition GluR2 containing receptors are Ca 2+ impermeable –Unless unedited Prominent in principle cell (e.g. cortical pyramidal neuron) synapses GluR1,3,4 calcium permeable –Calcium permeable AMPA receptors more common in interneurons

AMPAR have significant desensitization Contributes to rapid EPSC decay at some synapses

Spike/PSP interactions Hausser et al. Science Vol

EPSC/AP coupling Galaretta and Hestrin Science 292, 2295 (2001);

EPSP/spike coupling II Galaretta and Hestrin Science 292, 2295 (2001);

NMDA (glutamate) EPSP signaling, slower than with AMPA –  rise : 2-50 ms –  decay : ms cation dependent E NMDA 0 mV Significant Ca 2+ permeability NMDAR - necessary for many forms of long-term plasticity

NDMAR Blocked by physiological levels of [Mg 2+ ] o Voltage and [Mg 2+ ] o dependent Depolarization relieves block

Kainate receptors (glutamate) Roles are less well defined than AMPA/NMDA

Inhibitory ligand gated conductances GABA A –Fast IPSP signaling –  rise < 1ms –  decay : ms !, modulable –Cl - dependent –E GABAA range: –45.. –90 mV – Highly dependent on [Cl - ] i Which is in turn activity dependent NEURON can track this

Metabotropic receptors Many classes Conventional neurotransmitters, GABA, glutamate Peptide neurotransmitters, e.g. NPY, opioids, SST Often activate GIRKS –G-protein activated, inwardly-rectifying K + channels

mReceptors, cont’d. Inhibitory, hyperpolarizing responses. Can be excitatory, e.g. Substance P closes GIRKS Slow time course –e.g. GABA B responses can peak in > 30 ms and last 100s of ms Presynaptic & negatively coupled to GPCRs

Electrotonic synapses Transmembrane pores Resistive connection between the intracellular compartments of adjacent neurons Prominent in some inhibitory networks

Perisynaptic considerations Neurotransmitter uptake by glia or neurons Diffusion heterosynaptic effects extrasynaptic receptors Hydrolysis

Presynaptic receptor mediated alterations Mainly metabotropic –An exception is nicotinic AchR –Homosynaptic “autoreceptors” –Heterosynaptic receptors

Short term plasticity Dynamic changes in release probability –Likely mechanisms Ca 2+ accumulation in synaptic terminals Altered vesicle availability –To implement update P rel upon occurrence of a spike then continue to calculate state of P rel dependent on P 0 (resting probability) and  P(rel)

250 pA 2.5 ms Fran Shen

Dynamic-Clamp: Artificial Autaptic IPSCs Based on Fuhrmann, et al. J Neurophysiol 87: 140–148, 2002