Sex-dependent behavioral effects of Mthfr deficiency and neonatal GABA potentiation in mice

The methylenetetrahydrofolate reductase (Mthfr) gene and/or abnormal homocysteine–folate metabolism are associated with increased risk for birth defects and neuropsychiatric diseases. In addition, disturbances of the GABAergic system in the brain as well as Mthfr polymorphism are associated with neurodevelopmental disorders such as schizophrenia and autism.In the present study we performed behavioral phenotyping of male and female Mthfr mice (wild type and their heterozygous littermates). The present study addresses two main questions: (1) genetic susceptibility, as examined by effects of Mthfr deficiency on behavior (Experiment 1) and (2) possible gene–drug interactions as expressed by behavioral phenotyping of Mthfr-deficient mice neonatally exposed to the GABA potentiating drug GVG (Experiment 2).Newborn development was slightly influenced by Mthfr genotype per se (Experiment 1); however the gene–drug interaction similarly affected reflex development in both male and female offspring (Experiment 2). Hyperactivity was demonstrated in Mthfr heterozygous male mice (Experiment 1) and due to GVG treatment in both Wt and Mthfr+/− male and female mice (Experiment 2). The gene–environment interaction did not affect anxiety-related behavior of male mice (Experiment 2). In female mice, gene–treatment interactions abolished the reduced anxiety observed due to GVG treatment and Mthfr genotype (Experiment 2). Finally, recognition memory of adult mice was impaired due to genotype, treatment and the gene–treatment combination in a sex-independent manner (Experiment 2). Overall, Mthfr deficiency and/or GABA potentiation differentially affect a spectrum of behaviors in male and female mice.This study is the first to describe behavioral phenotypes due to Mthfr genotype, GVG treatment and the interaction between these two factors. The behavioral outcomes suggest that Mthfr deficiency modulates the effects of GABA potentiating drugs. These findings suggest that future treatment strategies should consider a combination of genotyping with drug regimens.

Research highlights▶ Newborn reflex development was slightly influenced by Mthfr+/− genotype and by the combination of Mthfr+/− genotype and the neonatal vigabatrin (GVG) administration, in a sex-independent manner. ▶ Anxiety: female but not male presented attenuated anxiety due to Mthfr+/− genotype and neonatal GVG treatment while their interaction abolished the effect. ▶ Motor: hyperactivity was demonstrated in untreated Mthfr+/− male but not female, whereas neonatal treatment with GVG induced hyperactivity in Wt and Mthfr+/− regardless of sex. ▶ Memory: recognition memory of adult mice was impaired due to Mthfr+/− genotype, neonatal GVG treatment and their combination in a sex-independent manner. ▶ Our findings suggest that future treatment strategies should consider a combination of genotyping with drug regimens.