CHRONIC MAGL INHIBITION SELECTIVELY RESTORES SEPTAL DENTATE GYRUS NEUROGENESIS IN ADULT TS65DN MICE, A GENETIC MODEL OF DOWN SYNDROME

Background: Down syndrome is associated with hippocampus-dependent cognitive impairment and reduced adult dentate gyrus (DG) neurogenesis. Chronic inhibition of monoacylglycerol lipase (MAGL) with JZL184 elevate brain levels of endocannabinoid 2-arachidonoylglycerol (2-AG), improves synaptic plasticity and long-term memory in Ts65Dn mice, but does not normalize anxiety-related behavior, suggesting region-specific effects within the hippocampus.
Methods: Middle-aged male Ts65Dn mice and euploid (2N) littermates received daily intraperitoneal injections of the MAGL inhibitor JZL184 (8 mg/kg) or vehicle for 20 days. Bromodeoxyuridine (BrdU, 100 mg/kg) was co-administered on treatment days 12–14, and BrdU-immunopositive cells were quantified in septal, intermediate, and temporal DG segments, and in suprapyramidal vs infrapyramidal blades, 7 days after the last BrdU injection.
Results: Ts65Dn mice showed a marked reduction in total number and density of BrdU-positive cells across the DG compared to 2N controls, accompanied by decreased granule cell layer (GCL) volume. JZL184 increased BrdU-positive cell number and density in Ts65Dn mice, thus restoring neurogenesis to near-control levels in the septal DG, with modest effects in the intermediate and no significant rescue in the temporal DG, while leaving 2N mice largely unaffected. In addition, the treatment partially restored the GCL volume.
Conclusions: Chronic MAGL inhibition with JZL184 normalizes adult hippocampal neurogenesis in Ts65Dn mice in a regionally selective manner, preferentially rescuing it in the cognition-related septal DG. These findings support endocannabinoid-targeted modulation as a promising, region-specific strategy to ameliorate hippocampal dysfunction and cognitive deficits associated with Down syndrome.
Supported by the National Institutes of Health, grant number R01HD100607