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

6. Threshold Erev V m = E Cl Excitatory Input Inhibitory Input Ex. + In.

7. Threshold Erev VmVm Excitatory Input Inhibitory Input Ex. + In. E Cl 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. At least 19 Different GABA A 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

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

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

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

14. 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)

15. Wallner et al. PNAS 100: 2003 Wei et al. J Neurosci 24: 2004 Low ethanol concentrations enhance tonic inhibition mediated by δ subunit- containing GABA A receptors Synaptic Receptors -  subunits Extrasynaptic Receptors -  subunits

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

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

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

19. CB1 Receptor blocker