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

Abstract

Imbalanced one carbon metabolism and aberrant autophagy is robustly reported in patients with autism. Polymorphism in the gene methylenetetrahydrofolate reductase (Mthfr), encoding for a key enzyme in this pathway is associated with an increased risk for autistic-spectrum-disorders (ASDs). Autistic-like core and associated behaviors have been described, with contribution of both maternal and offspring Mthfr+/− genotype to the different domains of behavior. Preconception and prenatal supplementation with methyl donor rich diet to human subjects and mice reduced the risk for developing autism and autistic-like behavior, respectively. Here we tested the potential of choline supplementation to Mthfr-deficient mice at young-adulthood to reduce behavioral and neurochemical changes reminiscent of autism characteristics. We show that offspring of Mthfr+/− mothers, whether wildtype or heterozygote, exhibit autistic-like behavior, altered brain p62 protein levels and LC3-II/LC3-I levels ratio, both, autophagy markers. Choline supplementation to adult offspring of Mthfr+/− mothers for 14 days counteracted characteristics related to repetitive behavior and anxiety both in males and in females and improved social behavior solely in male mice. Choline treatment also normalized deviant cortical levels of the autophagy markers measured in male mice. The results demonstrate that choline supplementation even at adulthood, not tested previously, to offspring of Mthfr-deficient mothers, attenuates the autistic-like phenotype. If this proof of concept is replicated it might promote translation of these results to treatment recommendation for children with ASDs bearing similar genetic/metabolic make-up.

Isolation-Induced Ultrasonic Vocalization in Environmental and Genetic Mice Models of Autism

“…Previous work in our labs showed that gestational exposure to the pesticide chlorpyrifos (C 9 H 11 C l3 NO 3 PS, CID2730, CPF) ( Lan et al, 2017 , 2019 ) and the Mthfr heterozygosity (Mthfr+/−) in mice ( Sadigurschi and Golan, 2018 ; Orenbuch et al, 2019 ; Agam et al, 2020 ) are both associated with impaired social preference and restricted or repetitive behavior, establishing them as mouse models of ASD with face validity. Mouse pups in both models present with developmental delay, in agreement with a neurodevelopmental delay observed in part of ASD patients ( Furlong et al, 2014 ; Shelton et al, 2014 ).…”

Early Life Nutrition and Mental Health: The Role of DNA Methylation

“…SAM formation is dependent on the levels of cellular micronutrients that play a role in these cycles, such as folate, methionine, betaine, choline, VitB2, VitB6 and VitB12 [ 12 , 13 ] ( Figure 1 ). These micronutrients can be derived from the diet, indicating that the quality of our diet across the lifespan will influence the one-carbon cycle and influence general health, including mental health [ 14 , 15 , 16 , 17 , 18 , 19 ].…”

Repetitive Restricted Behaviors in Autism Spectrum Disorder: From Mechanism to Development of Therapeutics

“…Furthermore, MTHFR polymorphism was associated with an increased risk of ASD, and the offspring of Mthfr + / − mice ( Pu et al, 2013 ), whether wild-type or heterozygous, exhibited autism-like behaviors. It is surprising that after 14 days of choline supplementation, the characteristics of RRBs were offset ( Agam et al, 2020 ). In addition, other supplementary treatments showed promising effects in ASD animals.…”