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Synaptic Transmission / Central Synapses II

Synaptic Transmission / Central Synapses II. Tom O’Dell Department of Physiology. todell@mednet.ucla.edu C8-161 (NPI), x64654. Lecture Topics. Inhibitory Synaptic Transmission : GABA GABA receptor subtypes Properties of phasic, tonic and slow inhibitory synaptic transmission

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Synaptic Transmission / Central Synapses II

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  1. Synaptic Transmission / Central Synapses II Tom O’Dell Department of Physiology todell@mednet.ucla.edu C8-161 (NPI), x64654

  2. Lecture Topics • Inhibitory Synaptic Transmission : GABA • GABA receptor subtypes • Properties of phasic, tonic and slow inhibitory synaptic • transmission • Sedative-hypnotics, anxiolytic, and recreational drugs

  3. Inhibitory Synaptic Transmission: GABA and Glycine

  4. Developmental Changes in Cl- Homeostasis

  5. Erev Threshold Vm ECl Excitatory Input Inhibitory Input Ex. + In. Most neurons in adult CNS, express Cl- extruding transporter KCC2

  6. Erev Threshold Vm = ECl Excitatory Input Inhibitory Input Ex. + In.

  7. Erev Threshold ECl Vm Excitatory Input Inhibitory Input Ex. + In. Immature neurons, accumulate Cl- due to the co-transporter NKCC1

  8. GABA and glycine receptors belong to the “cysteine-loop” family of ligand-gated ion channels

  9. Small particles = gsubunits Large particles =  subunits • At least 19 Different GABAA receptor Subunits! • (1-6, 1-3, 1-3, , , , , 1-3) • 60% are 1:2:2 • stoichiometry - 2:2;1 • Subunit composition regulates a number of different properties including sensitivity to modulators (benzodiazepines and neurosteroids) and cellular localization. •  subunit appears to be important for synaptic localization. Receptors that lack  and contain  subunits are extrasynaptic. Nusser et al. J. Neurosci, 1998

  10. Two Types of GABAA-Mediated Inhibition: Phasic and Tonic Phasic Phasic Tonic Farrant and Nusser, 2005

  11. Slow Inhibitory Synaptic Transmission is mediated by G protein-coupled GABA Receptors (GABAB)

  12. Barbiturates and Benzodiazepines Potently Enhance GABA Receptor Function Hoffman and Lupica, J Neurosci. 2000

  13. Alcohol is one of the oldest and most commonly used recreational drugs • Apparent per Capita (  14 years old) Alcohol Consumption in the United States: • 318 cans of beer • 77 glasses of wine • 179 “shots” (1.5 oz) of spirits Legal blood alcohol level in California is 0.08% (17 mM)

  14. Low ethanol concentrations enhance tonic inhibition mediated by δsubunit-containing GABAA receptors Wallner et al. PNAS 100: 2003 Synaptic Receptors -  subunits Extrasynaptic Receptors -  subunits Wei et al. J Neurosci 24: 2004

  15. DSI: Depolarization-induced suppression of Inhibition • Increases in postsynaptic calcium • Decreases in GABA release • Retrograde synaptic transmission

  16. THC Inhibits Inhibitory Synaptic Transmission Receptors: CB1(neuronal) and CB2 (peripheral) Agonist: WIN55,212-2; Antagonist: SR141716 Hajos et al Eur. J. Neurosci. 2000

  17. Neuronal Endocannabinoid Receptors (CB1) Makie and Katona, 2009

  18. CB1 Receptor blocker

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