Cannabidivarin mitigates motor and cognitive impairments in a female mouse model of Rett syndrome

Rett Syndrome (RTT, #312750 - OMIM) is a rare, progressive neurodevelopmental X-linked disorder, caused mostly by mutations in the gene for the methyl CpG binding protein 2 (MECP2). MECP2 is a transcriptional and epigenetic regulator that has been proposed to modulate neuronal development and adult neurogenesis, processes disrupted in both RTT patients and mouse models. Cannabidivarin (CBDV), a non-psychotropic cannabinoid, has recently been shown to promote adult neurogenesis through a mechanism mediated by transient receptor potential cation channel subfamily V member 1 (TRPV1). This study aimed to investigate the effects of chronic CBDV administration in a female RTT mouse model. Pre-symptomatic Mecp2^tm1.1Bird/J female mice underwent a chronic CBDV treatment (3 mg/kg/day), followed by behavioral tests to assess potential therapeutic effects. While CBDV did not prevent deficits in locomotor activity, it mitigated motor coordination impairments in RTT mice. Furthermore, the novel object recognition test suggested that CBDV treatment contributed to the preservation of cognitive function in these animals. Moreover, CBDV administration induced genotype-dependent differences in neural stem cell proliferation, indicating a potential vulnerability in adult hippocampal neurogenesis in Mecp2-deficient contexts. Taken together, these findings provide new insights into the role of CBDV in RTT and support for future research, highlighting its potential as a repurposed therapeutic agent.