Maternal and offspring methylenetetrahydrofolate‐reductase genotypes interact in a mouse model to induce autism spectrum disorder‐like behavior

Abstract

Individuals with autism constitute a variable population whose members are spread along the autism spectrum. Subpopulations within that spectrum exhibit other conditions, such as anxiety, intellectual disabilities, hyperactivity and epilepsy, with different severities and co‐occurrences. Among the genes associated with the increased risk for autism is the methylenetetrahydrofolate‐reductase (MTHFR) 677C>T polymorphism, which impairs one‐carbon (C1) metabolic pathway efficiency. The frequency of the MTHFR677TT homozygote is markedly higher among autism patients and their mothers than in the general population. Here, we report on the Mthfr heterozygous knockout (KO) mouse as a rodent model of autism that shows the contributions of maternal and offspring genotypes to the development of autistic‐like behaviors. Maternal Mthfr‐deficiency was associated with developmental delays in morphogenic features and sensory‐motor reflexes in offspring. In the adult male mouse, behaviors representing core autism symptoms, such as repetitive behavior and restricted interest, were affected by maternal genotype while social behaviors were affected by both maternal and offspring genotypes. In females and males, behaviors associated with autism such as memory impairment, social aggression and anxiety were affected by both the maternal and offspring Mthfr genotypes, with sex‐dependent differences. Mthfr‐deficient male mice with observable impacts on behavior presented a particular laminar disturbance in parvalbumin interneuron density and innervation in superficial and deep layers of the cingulate cortex. This mouse model of autism will help to elucidate the molecular mechanisms that predispose a significant subgroup of autistic patients to abnormal development and to distinguish between the in‐utero and autonomous factors involved in autism.

The influence of choline treatment on behavioral and neurochemical autistic-like phenotype in Mthfr-deficient mice

“…Similarly to our previous report 18 , male but not female Wt-Het mice processed nest-material less than the Wt-Wt group, p < 0.001; choline treatment counteracted this difference, p < 0.05. Choline treatment had an overall significant effect on all female groups, F 1,103 = 9.4, p = 0.003, so that it elevated processing in the Wt-Wt group and decreased it in the offspring of heterozygote dams.…”

“…The present study builds on our previous reports 18,19 of autism-like characteristics of offspring to mothers with heterozygote Mthfr-deficiency. The aims of the present study were (a) to substantiate these mice as an animalmodel of some of the facets of autistic-like behaviors and neurochemistry, and (b) to expand the study and investigate, in view of the role of MTHFR in the C1-metabolism, whether choline treatment might be beneficial in amending such aberrant parameters.…”

“…We recently reported that mice heterozygosity of Mthfr-KO causes ASD-like behavior, with a significant contribution of both the offspring and the maternal genotype 18 . Using a similar phenotyping protocol the possibility to normalize behavior in young adult offspring of Mthfr +/− mothers by choline supplementation was addressed.…”

“…Sample size was selected based on the biological variation expected. Variation was evaluated in similar experiments by studies performed in mice of the same colony 18,19 . 94 offspring, delivered in 24 litters were included in the study, not more than 2 pups per litter were included in an experimental group.…”

“…Scores (0-3) were given for material processing, centralization and symmetry. The volume of the nest was calculated by length × width × height 18 .…”