CB2 Cannabinoid Receptor Knockout in Mice Impairs Contextual Long-Term Memory and Enhances Spatial Working Memory

Abstract

Neurocognitive effects of cannabinoids have been extensively studied with a focus on CB1 cannabinoid receptors because CB1 receptors have been considered the major cannabinoid receptor in the nervous system. However, recent discoveries of CB2 cannabinoid receptors in the brain demand accurate determination of whether and how CB2 receptors are involved in the cognitive effects of cannabinoids. CB2 cannabinoid receptors are primarily involved in immune functions, but also implicated in psychiatric disorders such as schizophrenia and depression. Here, we examined the effects of CB2 receptor knockout in mice on memory to determine the roles of CB2 receptors in modulating cognitive function. Behavioral assays revealed that hippocampus-dependent, long-term contextual fear memory was impaired whereas hippocampus-independent, cued fear memory was normal in CB2 receptor knockout mice. These mice also displayed enhanced spatial working memory when tested in a Y-maze. Motor activity and anxiety of CB2 receptor knockout mice were intact when assessed in an open field arena and an elevated zero maze. In contrast to the knockout of CB2 receptors, acute blockade of CB2 receptors by AM603 in C57BL/6J mice had no effect on memory, motor activity, or anxiety. Our results suggest that CB2 cannabinoid receptors play diverse roles in regulating memory depending on memory types and/or brain areas.

Endocannabinoid system in neurodegenerative disorders

“…However, lack of CB2R (CB2RKO) does not accelerate the memory impairment in APP/PS1 mice, even though CB2RKO mice themselves exhibit memory impairments (Garcia‐Gutierrez et al . ; Li and Kim ,b). These findings together demonstrate that CB2Rs may assist in Aβ processing and thereby prevent neuroinflammation in AD (Koppel et al .…”

Cannabinoid receptor 1/2 double‐knockout mice develop epilepsy

“…Moreover, a majority of studies indicate that increased CB1 receptor activity is anticonvulsant and decreased activity is proconvulsant . On the other hand, Cnr2 −/− mice have not been reported to exhibit a seizure phenotype, although neurological deficits—including memory impairment and schizophrenia‐like symptoms—have been reported …”

“…5 On the other hand, Cnr2 À/À mice have not been reported to exhibit a seizure phenotype, 6 although neurological deficits-including memory impairment and schizophrenia-like symptoms-have been reported. 7 CB1 and CB2 receptors are activated by the endogenous cannabinoids anandamide and 2-arachidonoylglycerol. They are primarily coupled to the G i/o family of G-proteins.…”

Anxious behavior induces elevated hippocampal Cb2 receptor gene expression

“…The most abundant endocannabinoid, 2-AG, binds with equal affinity at both receptors, and has recently been shown to be important for extinction learning in hippocampal-dependent tasks (Kishimoto et al, 2015). In Cb 2 receptor knockout mice, contextual fear memory was impaired (Li and Kim, 2016a), which appears to be modulated through Cb 2 -NMDA interactions in dorsal hippocampus (Nasehi et al, 2017). In the hippocampi of transgenic mice overexpressing Cb 2 receptors, there was an increase in GABA A α 2 and GABA A γ 2 gene expression, indicating an increase in inhibitory output from the area (Garcia-Gutierrez and Manzanares, 2011).…”

“…While anxiety is not a sufficient stimulus on its own to upregulate hippocampal gene expression of Cb 2 receptors, when paired with fear conditioning gene expression for these receptors may be potently and rapidly upregulated as much as four-fold in both dorsal and ventral hippocampi. Upregulation occurred not only at both poles of the hippocampus, but also in regions containing granule and pyramidal cells (Li and Kim, 2015), suggesting that integrative events regulated by the hippocampus, such as learning (Li and Kim, 2016a) and anxiety, may be regulated comprehensively. Up- and downregulation of Cb 2 gene expression in the dCA 1 were significantly correlated with anxious and anxiolytic behaviors, respectively.…”