Transcript CB1
Synaptic Transmission / Central Synapses II Tom O’Dell Department of Physiology [email protected] C8-161 (NPI), x64654 Lecture Topics Inhibitory Synaptic Transmission : GABA • GABA receptor subtypes • Properties of phasic, tonic and slow inhibitory synaptic transmission • Sedative-hypnotics, anxiolytic, and recreational drugs Inhibitory Synaptic Transmission: GABA and Glycine Developmental Changes in Cl- Homeostasis Erev Threshold Vm ECl Excitatory Input Inhibitory Input Ex. + In. Most neurons in adult CNS, express Cl- extruding transporter KCC2 Erev Threshold Vm = ECl Excitatory Input Inhibitory Input Ex. + In. Erev Threshold ECl Vm Excitatory Input Inhibitory Input Ex. + In. Immature neurons, accumulate Cl- due to the co-transporter NKCC1 GABA and glycine receptors belong to the “cysteine-loop” family of ligand-gated ion channels • 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. Small particles = subunits Large particles = subunits Nusser et al. J. Neurosci, 1998 Two Types of GABAA-Mediated Inhibition: Phasic and Tonic Phasic Phasic Tonic Farrant and Nusser, 2005 Slow Inhibitory Synaptic Transmission is mediated by G protein-coupled GABA Receptors (GABAB) A B Control GABAB Blocker (Phaclofen) EPSP fast IPSP slow IPSP 5 mV 200 ms ec Barbiturates and Benzodiazepines Potently Enhance GABA Receptor Function Hoffman and Lupica, J Neurosci. 2000 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) Low ethanol concentrations enhance tonic inhibition mediated by δ subunitcontaining GABAA receptors Wallner et al. PNAS 100: 2003 Synaptic Receptors - subunits Extrasynaptic Receptors - subunits Wei et al. J Neurosci 24: 2004 DSI: Depolarization-induced suppression of Inhibition • Increases in postsynaptic calcium • Decreases in GABA release • Retrograde synaptic transmission THC Inhibits Inhibitory Synaptic Transmission Receptors: CB1(neuronal) and CB2 (peripheral) Agonist: WIN55,212-2; Antagonist: SR141716 Hajos et al Eur. J. Neurosci. 2000 Neuronal Endocannabinoid Receptors (CB1) Makie and Katona, 2009 CB1 Receptor blocker