Deletion of CB2 cannabinoid receptors reduces synaptic transmission and long‐term potentiation in the mouse hippocampus

Abstract

The effects of cannabinoids are mostly mediated by two types of cannabinoid receptors--CB1 receptors in the nervous system and CB2 receptors in the immune system. However, CB2 cannabinoid receptors have recently been discovered in the brain and also implicated in neurophysiological functions. The deletion of CB2 receptors in mice induces long-term memory deficits and schizophrenia-like behaviors, implying that endogenous activity of CB2 receptors might be involved in neuropsychiatric effects. Little is known about the cellular mechanisms by which physiological activation of CB2 receptors modulates neuronal functions. We aimed to determine how deletion of CB2 receptors in mice affects synaptic transmission and plasticity. Electrophysiological and morphological studies indicated that CB2 receptor knockout resulted in decreases in excitatory synaptic transmission, long-term potentiation, and dendritic spine density in the hippocampus. Our data imply that endogenous activity of CB2 receptors might contribute to the maintenance of synaptic functions and the expression of normal long-term potentiation. This study provides insights into the role of CB2 cannabinoid receptors in regulating cognitive functions such as long-term memory.

Cannabinoids and Vanilloids in Schizophrenia: Neurophysiological Evidence and Directions for Basic Research

“…Using a similar preparation, the same research group (Kim and Li, 2015) has demonstrated that chronic CB 2 receptor agonism elevates the frequency of quantal glutamate release in CA1, which does not occur in slices from schizophrenia-like CB 2 knockout mice. Slices from the same transgenic mice have also been reported to undergo weaker LTP in CA1 (Li and Kim, 2016; Figure 3D). Therefore, the hippocampus itself is prone to alterations in the mGluR/eCB interplay, which could contribute to downstream dysfunctions in mPFC, VTA, and other schizophrenia-relevant brain sites.…”

“…(C) In vitro assessment of mPFC synaptic plasticity and glutamatergic neurotransmission after adolescent WIN or early-life PCP exposure: association with schizophrenia-like symptoms (Lafourcade et al, 2007; Jew et al, 2013; Lovelace et al, 2014, 2015). (D) In vitro assessment of CA1 synaptic plasticity and eCB neurotransmission: relationships with schizophrenia risk factors and cannabinoid receptor activation (Du et al, 2013; Kim and Li, 2015; Li and Kim, 2016). 2-AG, 2-arachidonoyl-glycerol; adolesc, adolescent; antag, antagonism; dent, dentate; eCB-LTD, endocannabinoid long-term depression; ent, entorhinal; γ, gamma oscillations; hyperlocom, hyperlocomotion; KO, knockout; L, layer; LTP, long-term potentiation; meth, methamphetamine; mGluR, metabotropic glutamate receptors; mPFC, medial prefrontal cortex; NAc, nucleus accumbens; PCP, phencyclidine; relev, relevant; SCZ, schizophrenia; θ, theta oscillations; vHipp, ventral hippocampus; WIN, WIN 55,212-2.…”

“…Lastly, we mention three studies on the intra-hippocampal synaptic transmission (Du et al, 2013; Kim and Li, 2015; Li and Kim, 2016). According to Du et al (2013), chronic exposure to hippocampal organotypic cultures to neuregulin-1—whose over-expression is a risk factor for schizophrenia—increases the enzymatic degradation of 2-AG, resulting in weaker mGluR agonist-induced LTD in CA1.…”

Cannabinoid Modulation of Memory Consolidation in Rats: Beyond the Role of Cannabinoid Receptor Subtype 1

“…Despite the role of CB1 receptors in the regulation of neurophysiological functions has been extensively characterized, the presence of CB2 receptors in the brain is a novel finding, and their functional significance remain to be clarified. Electrophysiological and morphological studies strongly suggest that CB2 receptors are involved in synaptic transmission and plasticity (Li and Kim, 2016). Consequently, it has been demonstrated that CB2 receptors also modulate neurophysiological functions and behaviors such as anxiety (Garcia-Gutierrez et al, 2012), impulsive behaviors (Navarrete et al, 2012), vomiting (Van Sickle et al, 2005), and pain (Jhaveri et al, 2007; Anand et al, 2009; Han et al, 2013).…”

“…Traditionally, CB2 receptors have been thought to be exclusively expressed in the cells of the immune system (Munro et al, 1993). Despite their expression in neurons is still controversial, growing evidence strongly suggests that CB2 receptors are also expressed in the brain, and that they are involved in several neurobiological functions (Gong et al, 2006; Onaivi et al, 2006; Brusco et al, 2008; Garcia-Gutierrez et al, 2012; Navarrete et al, 2012; Li and Kim, 2016). Noteworthy, endocannabinoids, and their analogs, show binding affinity for other receptor families beyond the cannabinoid receptors, including the peroxisome proliferator-activated receptors (PPARs) (Fu et al, 2003; Bouaboula et al, 2005; O’Sullivan, 2007; Campolongo et al, 2009a; Luchicchi et al, 2010), and the transient receptor potential channels, especially vanilloid receptors transient receptor potential cation channel subfamily V member 1 (TRPV1) (Zygmunt et al, 1999; Di Marzo and De Petrocellis, 2010).…”