Chronic activation of CB2 cannabinoid receptors in the hippocampus increases excitatory synaptic transmission

Abstract

Key pointsr The effects of cannabinoids are primarily mediated by two types of cannabinoid receptors, CB1 receptors in the nervous system and CB2 receptors in the immune system. r Recent evidence indicates that CB2 receptors are also widely expressed in the brain and involved in neuropsychiatric functions, such as schizophrenia-like behaviours, anxiety, memory, vomiting and pain. r The cellular mechanisms by which CB2 receptors regulate neuronal functions are unknown. r We show that chronic activation of CB2 receptors in the hippocampus for 7-10 days increases excitatory synaptic transmission, whereas short-term activation of CB2 receptors has little effect on synaptic activity.r This study reveals a novel role of CB2 receptors in the brain, which is clearly distinct from that of CB1 receptors, and thus, will help us to understand better the diverse effects of cannabinoids in the nervous system. AbstractThe roles of CB1 cannabinoid receptors in regulating neuronal activity have been extensively characterized. Although early studies show that CB1 receptors are present in the nervous system and CB2 cannabinoid receptors are in the immune system, recent evidence indicates that CB2 receptors are also expressed in the brain. Activation or blockade of CB2 receptors in vivo induces neuropsychiatric effects, but the cellular mechanisms of CB2 receptor function are unclear. The aim of this study is to determine how activation of CB2 receptors present in the hippocampus regulates synaptic function. Here, we show that when organotypic cultures of rodent hippocampal slices were treated with a CB2 receptor agonist (JWH133 or GP1a) for 7-10 days, quantal glutamate release became more frequent and spine density was increased via extracellular signal-regulated kinases. Chronic intraperitoneal injection of JWH133 into mice also increased excitatory synaptic transmission. These effects were blocked by a CB2 receptor antagonist (SR144528) or absent from hippocampal slices of CB2 receptor knock-out mice. This study reveals a novel cellular function of CB2 cannabinoid receptors in the hippocampus and provides insights into how cannabinoid receptor subtypes diversify the roles of cannabinoids in the brain. Abbreviations ACSF, artificial cerebrospinal fluid; 2-AG, 2-arachidonoylglycerol; BSA, bovine serum albumin; CB1R, CB1 cannabinoid receptor; CB2R, CB2 cannabinoid receptor; 9 -THC, 9 -tetrahydrocannabinol; DIV, days in vitro; DSI, depolarization-induced suppression of inhibition; eEPSC, evoked excitatory postsynaptic current; eIPSC, evoked inhibitory postsynaptic current; ERK, extracellular signal-regulated kinase; fEPSP, field excitatory postsynaptic potential; I/O, input-output; KO, knock-out; LTP, long-term potentiation; mEPSC, miniature excitatory postsynaptic current; mIPSC, miniature inhibitory postsynaptic current; P r , probability of release; R m , membrane resistance; RRP, readily releasable pool; TBST, Tris-buffered saline with Tween 20.

Cannabinoid Receptor 2 as Antiobesity Target: Inflammation, Fat Storage, and Browning Modulation

“…Interestingly, it has been shown that only chronic activation of CB2 increases excitatory synaptic transmission, whereas its short-term activation has little effect on synaptic activity (32). A therapeutic use of CB2 as antiobesity target might presume a related chronic neuronal activation, that, in turn, increasing excitatory synaptic transmission, should facilitate the peripheral antiobesity effects without exerting remarkable psychotropic activity.…”

Intracellular GPCRs Play Key Roles in Synaptic Plasticity

“…In both regions, CB 2 receptors appear to be mostly neuronal, influencing excitatory synaptic transmission, plasticity, and long-term potentiation (80–82). Subcellular fractionation techniques, western blotting, binding assays and electrophysiology data from prefrontal cortex slices show that CB 2 receptors are located intracellularly and that 2-arachidonoylglycerol (2-AG) activation results in inositol triphosphate 3 (IP 3 ) receptor-dependent opening of Ca 2+ -activated chloride channels and decreased neuronal excitability (74, 83, 84).…”

Neuronal expression of CB2 cannabinoid receptor mRNAs in the mouse hippocampus

“…Chronic activation of CB2Rs increases excitatory synaptic transmission (Kim and Li, 2015), whereas acute activation of CB2Rs reduces inhibitory synaptic transmission (Morgan et al, 2009) and neuronal excitability (Patel et al, 2003; Sagar et al, 2005; den Boon et al, 2012; Zhang et al, 2014a). However, the cellular mechanisms of CB2R functions are unknown.…”

“…For investigation of the mechanisms, it is important to determine the cellular location of CB2Rs in the brain because it may suggest the signaling pathways of CB2Rs. For example, if hippocampal CB2Rs are expressed only in interneurons as suggested (Lanciego et al, 2011), the effects of CB2Rs on pyramidal cells (Kim and Li, 2015) might occur via intercellular signaling mechanisms, but this critical matter is yet to be identified.…”