PKC-GAMMA DELETION DISRUPTS CB1R SIGNALLING MECHANISMS RELEVANT FOR COGNITIVE PERFORMANCE

Cannabinoid type-1 receptor (CB1R) is responsible for most of the central effects of Δ9-tetrahydrocannabinol (THC) including memory impairment. Mammalian target of rapamycin (mTOR) signalling pathway is overactivated after THC administration leading to long-term memory deficits. Recent studies have identified the protein kinase C gamma (PKC-gamma) isoform as a relevant CB1R interactor in mouse hippocampus glutamatergic neurons. We investigated whether mice lacking PKC-gamma (PKC-gamma KO) would show altered CB1R expression, signalling and function including behavioural and molecular alterations relevant for cognitive effects of THC. Since the hippocampal distribution of PKC-gamma is subregion specific, with the highest expression in Cornu ammonis fields, we first analysed there CB1R density, activity and heterodimerization with serotonergic 5-HT2AR in PKC-gamma KO mice in comparison with wild-type (WT) mice. We found that PKC-gamma KO mice show modified CB1R density, activity, 5-HT2AR heterodimerization specifically in Cornu ammonis fields. Moreover, endocannabinoid system components related with 2-AG signalling, including protein levels of diacylglycerol lipase and monoacylglycerol lipase, were altered in the whole hippocampus preparations of mice lacking PKC-gamma. In addition, we found a decrease in phosphorylated CB1R(Ser317) and altered expression of mTOR signalling including an increase in phosphorylated S6(Ser235/236) in PKC-gamma KO mice. Finally, we assessed the effect of THC in PKC-gamma KO mice. We found that PKC-gamma KO mice are less sensitive to the hippocampal-dependent amnesic-like effects of THC while other pharmacological effects such as analgesia or hypothermia are not altered. Together, we reveal the significance of PKC-gamma isoform in CB1R expression, signalling and function relevant for cognitive performance.