The Endocannabinoid System Controls Key Epileptogenic Circuits in the Hippocampus

Abstract

Balanced control of neuronal activity is central in maintaining function and viability of neuronal circuits. The endocannabinoid system tightly controls neuronal excitability. Here, we show that endocannabinoids directly target hippocampal glutamatergic neurons to provide protection against acute epileptiform seizures in mice. Functional CB1 cannabinoid receptors are present on glutamatergic terminals of the hippocampal formation, colocalizing with vesicular glutamate transporter 1 (VGluT1). Conditional deletion of the CB1 gene either in cortical glutamatergic neurons or in forebrain GABAergic neurons, as well as virally induced deletion of the CB1 gene in the hippocampus, demonstrate that the presence of CB1 receptors in glutamatergic hippocampal neurons is both necessary and sufficient to provide substantial endogenous protection against kainic acid (KA)-induced seizures. The direct endocannabinoid-mediated control of hippocampal glutamatergic neurotransmission may constitute a promising therapeutic target for the treatment of disorders associated with excessive excitatory neuronal activity.

Impaired cannabinoid receptor type 1 signaling interferes with stress-coping behavior in mice

“…36 This finding appears particularly interesting in light of the compelling evidence that glutamatergic dysfunction can be related to psychiatric disorders (for review see Javitt 50 ). Taking recent evidence into account that CB1 receptors are, in addition to GABAergic terminals, as well prominently present on glutamatergic synapses 2,3 where they colocalize with VGLUT1 and influence glutamatergic transmission, 3 it was reasonable to hypothesize a potential dysregulation of VGLUT1 expression in CB1 À/À mice. Nevertheless, in situ hybridization of VGLUT1 mRNA in the brain revealed no alterations in CB1 À/À mice ( Figure 6).…”

“…36 Furthermore, VGLUT1 has been shown to be co-expressed with CB1 receptors in glutamatergic neurons of the cortex and hippocampus. 3 Therefore, we evaluated male CB1 þ / þ and CB1 À/À mice for their VGLUT1 mRNA expression levels under basal conditions in order to assess if a downregulation of VGLUT1 coincides with the depressionlike FST phenotype in CB1 À/À mice. However, no significant genotype differences in VGLUT1 mRNA expression could be detected in the cortex or any sub-field of the dorsal or ventral hippocampus ( Figure 6; statistics not shown).…”

“…In situ hybridizations for BDNF and VGLUT1 mRNA were performed as previously described. 2,3 Densitometric analyses were performed on autoradiographic films using the NIH Image software (http://rsb.info.nih.gov/nih-image/Default.html).…”

“…1 They bind to presynaptically localized cannabinoid type 1 (CB1) receptors where they constrain the activity of various neurotransmitter systems, including glutamate, 2 GABA, 3 acetylcholine, 4 noradrenaline (NA) 5 and serotonin (5-HT). 5,6 The endocannabinoid system has, thus, been recognized as one of the major neuromodulatory systems of the brain that functions to maintain the homeostasis of various states including mood and emotion.…”

Cannabinoid-mediated short-term plasticity in hippocampus

“…Also, it has been hypothesised that suppression of excitation is the mode of action of the anti-convulsant effects of CBs (Blair, 2006;Hajos and Freund, 2002). This hypothesis has been supported in a study by Monory et al (Monory et al, 2006) where deletion of CB 1 receptors from glutamatergic terminals was shown to be pro-convulsant whereas the deletion of CB 1 receptors from GABAergic cells did not change seizure behaviour. Monory et al (2006) suggest that either DSI is not induced due to high pre-synaptic firing or because it is overwritten by DSE.…”