Mechanisms of Cannabinoid Inhibition of GABA_ASynaptic Transmission in the Hippocampus

Abstract

The localization of cannabinoid (CB) receptors to GABAergic interneurons in the hippocampus indicates that CBs may modulate GABAergic function and thereby mediate some of the disruptive effects of marijuana on spatial memory and sensory processing. To investigate the possible mechanisms through which CB receptors may modulate GABAergic neurotransmission in the hippocampus, whole-cell voltage-clamp recordings were performed on CA1 pyramidal neurons in rat brain slices. Stimulus-evoked GABA(A) receptor-mediated IPSCs were reduced in a concentration-dependent manner by the CB receptor agonist WIN 55,212-2 (EC(50) of 138 nM). This effect was blocked by the CB1 receptor antagonist SR141716A (1 microM) but not by the opioid antagonist naloxone. In contrast, evoked GABA(B)-mediated IPSCs were insensitive to the CB agonist. WIN 55,212-2 also reduced the frequency of spontaneous, action potential-dependent IPSCs (sIPSCs), without altering action potential-independent miniature IPSCs (mIPSCs), measured while sodium channels were blocked by tetrodotoxin (TTX). Blockade of voltage-dependent calcium channels (VDCCs) by cadmium also eliminated the effect of WIN 55,212-2 on sIPSCs. Depolarization of inhibitory terminals with elevated extracellular potassium caused a large increase in the frequency of mIPSCs that was inhibited by both cadmium and WIN 55,212-2. The presynaptic effect of WIN 55,212-2 was also investigated using the potassium channel blockers barium and 4-aminopyridine. Neither of these agents significantly altered the effect of WIN 55,212-2 on evoked IPSCs. Together, these data suggest that presynaptic CB1 receptors reduce GABA(A)- but not GABA(B)-mediated synaptic inhibition of CA1 pyramidal neurons by inhibiting VDCCs located on inhibitory nerve terminals.

Endocannabinoid‐mediated short‐term synaptic plasticity: depolarization‐induced suppression of inhibition (DSI) and depolarization‐induced suppression of excitation (DSE)

“…CB1R activation does not seem to affect mIPSCs (Hoffman & Lupica, 2000;Chen et al, 2003, but see later) and, likewise, hippocampal DSI was reported to affect 12 M.A. Diana & A. Marty DSI/DSE: two forms of CB1R-mediated plasticity mIPSCs frequency only minimally (Pitler & Alger, 1994).…”

“…Moreover, DSI spread between pyramidal cells takes place only at short distances (up to 20 mm), indicating that only passive diffusion of cannabinoids, but not a modulation of presynaptic firing, is involved ). Thus, CB1R action on GABAergic interneurons could simply be explained by an inhibition of presynaptic calcium conductances (Hoffman & Lupica, 2000).…”

The Psychotomimetic Effects of Intravenous Delta-9-Tetrahydrocannabinol in Healthy Individuals: Implications for Psychosis

“…These GABAergic interneurons are believed to orchestrate fast synchronous oscillations in the gamma range, a critical process in synchronizing pyramidal cell activity (Hajos et al, 2000;Hoffman and Lupica, 2000). Gamma oscillations are synchronized over long distances in the brain and are hypothesized to 'bind' together sensory perceptions and to play a role in cognition (reviewed in Wilson and Nicoll, 2002).…”

“…Abnormalities in gamma band synchronization have been reported in schizophrenia (Spencer et al, 2003). Activation of these presynaptic CB1Rs reduces GABA release by interneurons (Sullivan, 1999;Katona et al, 1999a), which in turn would disrupt the synchronization of pyramidal cell activity (Wilson and Nicoll, 2002;Hoffman and Lupica, 2000), thereby interfering with associative functions, disrupting normal gating mechanisms, and eventually inducing psychotic symptoms. …”

GABAergic interneurons are the targets of cannabinoid actions in the human hippocampus

“…Moreover, cannabinoids were shown to inhibit GABA release by activating these receptors and suppressing GABA A -receptor mediated inhibitory postsynaptic currents in CA1 pyramidal cells. 19,20 However, beside the expression in GABAergic neurons, some electrophysiological experiments also suggested that glutamatergic principal cells may carry presynaptic CB1 receptors, which may explain their interference with long-term potentiation induction. 4,31,38 In contrast, CB1 mRNA was only found in these principal cells at low levels, slightly above the background, or low to moderate levels in the aged human hippocampus.…”