Increased susceptibility to mild neonatal stress in MTHFR deficient mice.

Early life stress is shown to have a life-span outcome on human and animal behavior, increasing the risk for psychopathology. The gene methylenetetrahydrofolate reductase (MTHFR), which encodes for a key enzyme in one carbon metabolism, shows a high prevalence of polymorphism in patients with developmental disorders. Here we examined the hypothesis that MTHFR deficiency results in an increased susceptibility of the developing brain to mild neonatal stress (NS). Mild NS failed to alter corticosterone levels in young and adult Wt mice. However, an elevated level of corticosterone was found in the MTHFR deficient-NS female, exemplifying enhanced sensitivity to NS. Behavioral phenotyping of Wt and MTHFR deficient mice provides evidence that the effect of mild NS may be amplified by the MTHFR deficient genotype. Distinct behavioral characteristics were altered in male and female mice. In general, three patterns of influence on mice behavior were observed: (1) an additive suppressive effect of NS and MTHFR deficiency on exploration and activity was evident in females; (2) stress related parameters were significantly sensitive to genotype in females, presenting an interaction between genotype and sex; (3) various aspects of behavior in a social setting were modified preferably in males by genotype, NS and the interaction between the two, while females exhibited a smaller effect that was restricted to NS with no genotype effect. Overall, our results support an interaction between mild NS, the MTHFR genotype and sex. We suggest using this animal model to study the molecular mechanism linking these two risk factors and their involvement in neurodevelopmental disorders such as schizophrenia and autism.

Specific neurodevelopmental damage in mice offspring following maternal inflammation during pregnancy.

Intrauterine inflammation is a major risk for offspring neurodevelopmental brain damage and may result in cognitive limitations and poor cognitive and perceptual outcomes. Pro-inflammatory cytokines, stimulated during inflammatory response, have a pleotrophic effect on neurons and glia cells. They act in a dose-dependent manner, activate cell-death pathways and also act as trophic factors. In the present study, we have examined in mice the effect of short, systemic maternal inflammation on fetal brain development. Maternal inflammation, induced by lipopolysaccharide (LPS) at gestation day 17, did not affect morphogenic parameters and reflex development during the first month of life. However, maternal inflammation specifically increased the number of pyramidal and granular cells in the hippocampus, as well as the shrinkage of pyramidal cells, but not of the granular cells. No additional major morphological differences were observed in the cerebral cortex or cerebellum. In accordance with the morphological effects, maternal inflammation specifically impaired distinct forms of learning and memory, but not motor function or exploration in the adult offspring. The specific deficiency observed, following maternal inflammation, may suggest particular sensitivity of the hippocampus and other associated brain regions to inflammatory factors during late embryonic development.