Cannabinoids inhibit hippocampal GABAergic transmission and network oscillations

Abstract

Using a new antibody developed against the C-terminus of the cannabinoid receptor (CB1), the immunostaining in the hippocampus revealed additional axon terminals relative to the pattern reported previously with an N-terminus antibody. Due to a greater sensitivity of this antibody, a large proportion of boutons in the dendritic layers displaying symmetrical (GABAergic) synapses were also strongly immunoreactive for CB1 receptors, as were axon terminals of perisomatic inhibitory cells containing cholecystokinin. Asymmetrical (glutamatergic) synapses, however, were always negative for CB1. To investigate the effect of presynaptic CB1 receptor activation on hippocampal inhibition, we recorded inhibitory postsynaptic currents (IPSCs) from principal cells. Bath application of CB1 receptor agonists (WIN55,212-2 and CP55,940) suppressed IPSCs evoked by local electrical stimulation, which could be prevented or reversed by the CB1 receptor antagonist SR141716A. Action potential-driven IPSCs, evoked by pharmacological stimulation of a subset of interneurons, were also decreased by CB1 receptor activation. We also examined the effects of CB1 receptor agonists on Ca2+-independent miniature IPSCs (mIPSC). Both agonists were without significant effect on the frequency or amplitude of mIPSCs. Synchronous gamma oscillations induced by kainic acid in the CA3 region of hippocampal slices were reversibly reduced in amplitude by the CB1 receptor agonist CP 55,940, which is consistent with an action on IPSCs. We used CB1-/- knock-out mice to confirm the specificity of the antibody and of the agonist (WIN55,212-2) action. We conclude that activation of presynaptic CB1 receptors decreases Ca2+-dependent GABA release, and thereby reduces the power of hippocampal network oscillations.

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

“…In the hippocampus, CB-1R are located primarily on cholecystokinin containing GABAergic interneurons (Hajos et al, 2000;Katona et al, 2000Katona et al, , 1999aKatona et al, , 1999bTsou et al, 1999). 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).…”

“…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).…”

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

“…The pattern for hippocampal DSE is further complicated by the uncertainties on the CB receptor isoform mediating the cannabinoid response. In fact, although this is still a disputed issue (Marsicano & Lutz, 1999: Marsicano et al, 2003, some of the presently available evidence suggests that CB1Rs are not present on glutamatergic terminals onto CA1 pyramidal cell (Katona et al, 1999;Tsuo et al, 1999;Hajos et al, 2000), and that a so far uncloned CB receptor might provide the sensitivity to cannabinoids (Hajos et al, 2001;Breivogel et al, 2001). Independently of this issue, the take home message remains that, in the hippocampus, cannabinoidmediated retrograde inhibition appears to pertain mainly to GABAergic synapses .…”

Cannabinoids, electrophysiology, and retrograde messengers: Challenges for the next 5 years

“…Subsequent work from several labs has extended these studies to central nervous system (CNS) neurons and provides a mechanistic basis for attenuation of neurotransmission by CB1 activation. 5 Presumed mechanisms generally invoke inhibition of presynaptic (eg, N-and P/Q-type) calcium channels 18 , 19 but may also involve activation of potassium channels and CB1-mediated direct inhibition of the vesicular release machinery. 6 …”

“…Indeed, several studies have shown this to be the case. [5][6][7] Given the locations and actions of cannabinoid receptors, one would expect the presence of an endogenous ligand, a prediction that has been borne out. Specifi cally, 2 families of endocannabinoids have been extensively characterized.…”