Research reportIncreased susceptibility to mild neonatal stress in MTHFR deficient mice
Introduction
Polymorphism in genes encoding enzymes of one carbon (C1) metabolism was found to increase the risk for neuropsychiatric disorders such as schizophrenia and autism spectrum disorders. One gene of this cycle, methylenetetrahydrofolate reductase (MTHFR), shows a high prevalence of polymorphism in autistic patients and/or mothers [1], [2], [3]. Similarly, the maternal MTHFR 677C>T polymorphism was associated with increased risk for schizophrenia in their children [4]. It is possible that the low activity of MTHFR combined with other genetic and environmental factors contributes to the developmental outcome.
Additional factors can interfere with the brain's developmental program, the most significant being those associated with the immediate environment of the fetus and the newborn. Adverse stimuli during sensitive periods when the neuron-endocrine circuit of the stress response is being established have long-lasting impacts on the response to stressors in later life. Effects of maternal care and maternal separation on various aspects of the stress response and cognitive function were described more than 40 years ago [5], [6], [7]. Initial evidence from the last decade has suggested that stable modifications of the DNA, such as DNA methylation, demethylation, and acetylation, play important roles in the maintenance of the long-term effects of early life events on the regulation of gene expression [8], [9].
MTHFR deficient mice (MTHFR+/−) exhibit alterations in anxiety, activity, and social behavior [10], [11]. Moreover, the MTHFR deficient genotype interacts with early life exposure to GABA potentiating drugs to modify mice behavior and the levels of proteins associated with synapse function and plasticity [11].
We hypothesize that the metabolic stress induced by the MTHFR deficient genotype results in the increased susceptibility of the developing brain to mild NS. To examine this hypothesis, male and female MTHFR+/+ and MTHFR+/− newborns were subjected to daily mild stress during early postnatal life. Behavioral outcome and corticosterone level were tested at 3 months of age. A significant interaction between the MTHFR genotype, mild NS and gender was found to modulate adult mice behavior in the contexts of anxiety-related behavior and social settings.
Section snippets
Mouse colony
Mice on a Balb/cAnNCrlBR background were studied (mice were kindly provided by Prof. Rima Rozen, McGill University, Montreal, QC, Canada) [12]. The mouse colony was maintained in the animal facility of Ben-Gurion University of the Negev on a 12:12 h light/dark schedule with food and water provided ad libitum. All experiments were carried out in accordance with the National Institutes of Health guidelines for the care and use of laboratory animals (NIH Publications No. 8023, revised 1978) and
Effects of MTHFR genotype and mild NS on newborn behavior
Development of newborn righting reflex on days when mild NS was induced was analyzed to assess the short-term effect of the daily injection. Comparisons between Wt-NS and MTHFR+/−-NS mice revealed similar reflex development in both males and females, and by postnatal day 11, the reflex was performed in less than one second by all mice (Fig. 1A and E). Stress was induced in young mice at the age of 1 month by placing the mice on an elevated round transparent platform for duration of 4 min. The
Discussion
This report provides detailed behavioral phenotyping of the interaction between MTHFR deficiency and mild NS in a mouse model. In both humans and rodents, each factor was previously reported to increase the risk for behavioral impairment in different domains of behavior [10], [22], [23]. We showed here for the first time that the effect of extremely mild NS may be amplified by the MTHFR deficient genotype. Moreover, we found that distinct aspects of behavior were differentially altered in male
Acknowledgements
We thank Prof. Hagit Cohen and Dr. Nitzan Kozolovski for their dedicated help with the analysis of corticosterone concentrations in mice urine, Miss Rasha Huleihel for her assistance in behavioral tests and Mr. Itay Kezurer for his assistance with the graphical representation of mice behavior.
References (36)
- et al.
Modification of corticosterone response curve as a function of handling in infancy
Physiology and Behavior
(1969) - et al.
Maternal programming of steroid receptor expression and phenotype through DNA methylation in the rat
Frontiers in Neuroendocrinology
(2005) - et al.
Association of plasma homocysteine and methylenetetrahydrofolate reductase C677T gene variant with schizophrenia: a Chinese Han population-based case-control study
Psychiatry Research
(2009) - et al.
Mouse behavioral tasks relevant to autism: phenotypes of 10 inbred strains
Behavioural Brain Research
(2007) - et al.
The effects of an early stressful life event on sensorimotor gating in adult rats
Schizophrenia Research
(1998) - et al.
Early life stress increases anxiety-like behavior in Balbc mice despite a compensatory increase in levels of postnatal maternal care
Hormones and Behavior
(2010) - et al.
Mouse strain differences in plasma corticosterone following uncontrollable footshock
Pharmacology Biochemistry and Behavior
(1990) BALB/c mice: low sociability and other phenotypes that may be relevant to autism
Behavioural Brain Research
(2007)- et al.
The effects of postnatal handling on the development of the glucocorticoid receptor systems and stress recovery in the rat
Progress in Neuro-Psychopharmacology and Biological Psychiatry
(1985) - et al.
Lasting epigenetic influence of early-life adversity on the BDNF gene
Biological Psychiatry
(2009)
The MTHFR 677C--> T polymorphism and behaviors in children with autism: exploratory genotype–phenotype correlations
Autism Research
Aberrations in folate metabolic pathway and altered susceptibility to autism
Psychiatric Genetics
Prenatal vitamins, one-carbon metabolism gene variants, and risk for autism
Epidemiology
A meta-analysis of the MTHFR C677 T polymorphism and schizophrenia risk
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
Long-term consequences of neonatal rearing on central corticotropin-releasing factor systems in adult male rat offspring
Neuropsychopharmacology
Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat
Proceedings of the National Academy of Science
Epigenetic programming by maternal behavior
Nature Neuroscience
Sex-dependent behavioral effects of Mthfr deficiency and neonatal GABA potentiation in mice
Behavioural Brain Research
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