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Understanding Interneuronal Communication: Electrochemical Signaling and Synaptic Mechanisms

This lecture by John Huguenard explores the complexities of interneuronal communication through electrochemical signaling. It discusses synaptic mechanisms, including calcium-dependent neurotransmitter release and the probabilistic nature of synaptic release. The influence of action potentials on neurotransmitter release and the response variability at synaptic terminals are highlighted. Additionally, the function of ionotropic receptors, including AMPA and NMDA receptors, in excitatory and inhibitory signaling is examined, along with their roles in synaptic plasticity. The lecture provides insights into the dynamics of neurotransmitter release and postsynaptic response properties.

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Understanding Interneuronal Communication: Electrochemical Signaling and Synaptic Mechanisms

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Presentation Transcript

  1. Nens220, Lecture 6 Interneuronal communication John Huguenard

  2. Electrochemical signaling

  3. Synaptic Mechanisms • Ca2+ dependent release of neurotransmitter • Normally dependent on AP invasion of synaptic terminal • Probabilistic

  4. 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

  5. Binomial probability

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

  7. The probability of a ligand gated channel be open (Ps) 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

  8. Three major classes of ligand gated conductances: ligands • Excitatory • Glutamate • AMPA/Kainate receptors (fast) • NMDA receptors (slow) • Inhibitory • Gamma amino butyric acid GABAA receptors

  9. AMPA (glutamate) • Fast EPSP signaling • trise < 1ms • tdecay : 1..10 ms • Cation dependent • EAMPA 0 mV.

  10. Ca2+ permeability: AMPAR • Depends on molecular composition • GluR2 containing receptors are Ca2+ 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

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

  12. Spike/PSP interactions Hausser et al. Science Vol. 291. 138 - 141

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

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

  15. NMDA (glutamate) • EPSP signaling, slower than with AMPA • trise : 2-50 ms • tdecay : 50-300 ms • cation dependent • ENMDA 0 mV • Significant Ca2+ permeability • NMDAR - necessary for many forms of long-term plasticity

  16. NDMAR Blocked by physiological levels of [Mg2+]o • Voltage and [Mg2+]o dependent • Depolarization relieves block

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

  18. Inhibitory ligand gated conductances • GABAA • Fast IPSP signaling • trise < 1ms • tdecay : 1.. 200 ms !, modulable • Cl- dependent • EGABAA range: –45 .. –90 mV • Highly dependent on [Cl-]i • Which is in turn activity dependent • NEURON can track this

  19. 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

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

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

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

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

  24. Short term plasticity • Dynamic changes in release probability • Likely mechanisms • Ca2+ accumulation in synaptic terminals • Altered vesicle availability • To implement • update Prel upon occurrence of a spike • then continue to calculate state of Prel dependent on P0 (resting probability) and tP(rel)

  25. 250 pA 2.5 ms 250 pA Fran Shen

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

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