Cellular specificity and sexual dimorphism of hippocampal CB1 receptors on behavioral processes

In this work, we want to dissect the specific and sex-dependent role of CB1 signalling in different cell types and its impact on hippocampal functions such as navigation or memory. A specific Cre-mediated CB1 deletion on neurons (excitatory and inhibitory), astrocytes, or interneurons in CB1-flox males and females was performed. Viral vectors (AAV-Cre) were injected bilaterally into the hippocampus of these mice. The Barnes maze was used for learning, memory, navigation and the Novel Object Recognition Test (NORT) for recognition memory. Anxiety-like behavioural protocols were also performed before cognitive evaluation to establish an emotional baseline. We then analysed the inhibitory cell subpopulations by immunofluorescence image analysis. CB1-flox mice carrying a hippocampal CB1 deletion in different cell types presented different changes in cognitive processes compared to control littermates. CB1 deletion from all neurons produced a specific decrease in the spatial strategy in the Barnes Maze, and an impairment in the recognition memory in males. Specific CB1 deletion from hippocampal interneurons affected the innate emotional response in females. Hippocampal CB1 deletion in astrocytes presented an impairment in learning and memory performance. Field excitatory postsynaptic potentials (fEPSPs) were evoked in CA1 stratum radiatum by stimulating Schaffer collaterals (SCs) with a tetanic stimulation (4 trains at 100 Hz for 1 s; 30 s intervals) to induce long term potentiation (LTP). This plasticity was absent neuronal or astrocytic CB1 deleted males. Finally, different expression patterns of hippocampal cells were observed and quantified in the immunohistochemistry assays.