Age differences in the role of the cannabinoid type 1 receptor on glutamatergic neurons in habituation and spatial memory acquisition

AimsAging is typically linked with a decline in memory performance and alterations in neural integrity. In pathological aging such as Alzheimer's disease, these effects are aggravated. Studies using cannabinoid CB1 receptor-deficient mice have shown a role of the endocannabinoid system in memory processing and neuroprotection. As the CB1 receptor is expressed in various neuronal populations, in this study, we aimed at investigating the consequences of CB1 receptor gene inactivation in cortical glutamatergic neurons in mice (Glu-CB1-KO) in regard to age-related alterations in spatial memory performance.Main methodsJuvenile (5.5–7.5 weeks), adult (5.5–7 months), and old (11.5–14 months) Glu-CB1-KO and Glu-CB1-WT mice were compared in two spatial learning tasks, the Morris Water Maze (MWM) using both visible and hidden platforms, and the Water Cross Maze (WCM).Key findingsIn the MWM with a visible platform, adult and old Glu-CB1-KO mice showed a delayed acquisition of the task, suggesting an age-dependent function of the endocannabinoid system in habituation. Juvenile and adult Glu-CB1-KO mice exhibited increased time and path length to the hidden platform in the MWM. However, these characteristics were accompanied by increased thigmotaxis in both age groups, suggesting anxiety-like behavior as a confounding factor. To exclude this possible bias, the animals were tested in a simplified spatial learning assay, the WCM, revealing a decreased accuracy of juvenile but not of adult Glu-CB1-KO to find the platform, therefore strongly suggesting spatial memory impairment in juvenile mice.SignificanceOur results suggest an age-dependent role of the CB1 receptor on cortical glutamatergic neurons in both habituation and spatial learning.