Neuroglial CB1 receptors modulate hippocampal processes in a sex-dependent manner

Background Navigation and memory are hippocampal functions that are essential for survival. One of the key modulators of hippocampal activity is the endocannabinoid system through the cannabinoid receptor type 1 (CB1). CB1 is widely expressed in various types of hippocampal cells. While it is known that CB1 participates in memory processes, its specific roles in different cell types and differences between sexes remain unclear. Methods This study investigates the cell- and sex-specific modulation of navigation and memory by CB1 receptors. To this end, we selectively deleted CB1 receptors from hippocampal neurons or astrocytes in adult male and female mice. We then assessed its effect on a comprehensive range of behaviors, including innate emotional responses, memory, navigation, and nesting. Results Deletion of CB1 from hippocampal principal cells or astrocytes produced significant changes in innate emotional behavior and novel object recognition in both sexes. Conversely, CB1 receptor deletion from all neurons produced deficits in spatial navigation exclusively in males. Interestingly, synaptic plasticity was impaired in both male and female mice lacking CB1 receptors from GFAP-positive cells. Nest-building behavior was only affected in males carrying the CB1 deletion in CAMK-positive cells. Conclusion In conclusion, our findings show that neuronal CB1 receptors are critical for spatial navigation in males, while astrocytic CB1 receptors play a key role in memory processes in both males and females.