Hippocampal Deletion of CB1 Receptor Impairs Social Memory and Leads to Age-Related Changes in the Hippocampus of Adult Mice

Endocannabinoid system activity declines with age in the hippocampus, along with the density of the cannabinoid receptor type-1 (CB1). This process might contribute to brain ageing, as previous studies showed that the constitutive deletion of the CB1 receptor in mice leads to early onset of memory deficits and histological signs of ageing in the hippocampus including enhanced pro-inflammatory glial activity and reduced neurogenesis. Here we asked whether the CB1 receptor exerts its activity locally, directly influencing hippocampal ageing or indirectly, accelerating systemic ageing. Thus, we deleted the CB1 receptor site-specifically in the hippocampus of 2-month-old CB1(flox/flox) mice using stereotaxic injections of rAAV-Cre-Venus viruses and assessed their social recognition memory four months later. Mice with hippocampus-specific deletion of the CB1 receptor displayed a memory impairment, similarly as observed in constitutive knockouts at the same age. We next analysed neuroinflammatory changes in the hippocampus, neuronal density and cell proliferation. Site-specific mutant mice had enhanced glial cell activity, up-regulated levels of TNF alpha in the hippocampus and decreased cell proliferation, specifically in the subgranular zone of the dentate gyrus. Our data indicate that a local activity of the CB1 receptor in the hippocampus is required to maintain neurogenesis and to prevent neuroinflammation and cognitive decline.

Automated summary

The decline in endocannabinoid system activity and CB1 receptor density in the hippocampus with age may contribute to brain ageing. This study showed that site-specific deletion of the CB1 receptor in the hippocampus resulted in memory impairment, neuroinflammation, reduced neurogenesis, and decreased cell proliferation. These findings suggest that local CB1 receptor activity is necessary for maintaining neurogenesis and preventing neuroinflammation and cognitive decline.