Cell type-specific genetic reconstitution of CB1 receptor subsets to assess their role in exploratory behaviour, sociability, and memory.

Several studies support the notion that exploratory behaviour depends on the functionality of the cannabinoid type 1 (CB1) receptor in a cell type-specific manner. Mice lacking the CB1 receptor in forebrain GABAergic or dorsal telencephalic glutamatergic neurons have served as essential tools revealing the necessary CB1 receptor functions in these two neuronal populations. However, whether these specific CB1 receptor populations are also sufficient within the endocannabinoid system for wild-type-like exploratory behaviour has remained unknown. To evaluate cell-type-specific sufficiency of CB1 receptor signalling exclusively in dorsal telencephalic glutamatergic neurons (Glu-CB1-RS) or in forebrain GABAergic neurons (GABA-CB1-RS), we utilised a mouse model in which CB1 receptor expression can be reactivated conditionally at endogenous levels from a complete CB1-KO background. The two types of conditional CB1-rescue mice were compared with CB1 receptor-deficient [no reactivation (Stop-CB1)] and wild-type [ubiquitous reactivation of endogenous CB1 receptor (CB1-RS)] controls to investigate the behavioural consequences. We evaluated social and object exploratory behaviour in four different paradigms. Remarkably, the reduced exploration observed in Stop-CB1 animals was rescued in Glu-CB1-RS mice and sometimes even surpassed CB1-RS (wild-type) exploration. In contrast, GABA-CB1-RS animals showed the lowest exploratory drive in all paradigms, with an even stronger phenotype than Stop-CB1 mice. Interestingly, these effects weakened with increasing familiarity with the environment, suggesting a causal role for altered neophobia in the observed phenotypes. Taken together, using our genetic approach, we were able to substantiate the opposing role of the CB1 receptor in dorsal telencephalic glutamatergic versus forebrain GABAergic neurons regarding exploratory behaviour.