title: Glutamatergic synapse protein composition of wild-type mice is sensitive to in utero MTHFR genotype and the timing of neonatal vigabatrin exposure.
abstract: The enzyme methylenetetrahydrofolate-reductase (MTHFR) is part of the homocysteine and folate metabolic pathways. In utero, Mthfr-deficient environment has been reported as a risk factor for neurodevelopmental disorders such as autism and neural tube defects. Neonatal disruption of the GABAergic system is also associated with behavioral outcomes. The interaction between Mthfr deficiency and neonatal exposure to the GABA-potentiating drug vigabatrin (GVG) in mice alters anxiety, memory, and social behavior in a gender-dependent manner. In addition, a gender-dependent enhancement of proteins implicated in excitatory synapse plasticity in the cerebral cortex was shown. Here we show that in utero MTHFR deficiency is sufficient to alter the levels of glutamate receptor subunits GluR1, GluR2, and NR2B in the cerebral cortex and hippocampus of adult offspring with a WT genotype. In addition, FMRP1, CAMKII α and γ, and NLG1 levels in WT offspring were vulnerable to the in utero genotype. These effects depend on brain region and the cellular compartment tested. The effect of in utero MTHFR deficiency varies with the age of neonatal GVG exposure to modify GluR1, NR2A, reelin, CAMKII α, and NLG1 levels. These changes in molecular composition of the glutamatergic synapse were associated with increased anxiety-like behavior. Complex, multifactorial disorders of the nervous system show significant association with several genetic and environmental factors. Our data exemplify the contribution of an in utero MTHFR-deficient environment and early exposure to an antiepileptic drug to the basal composition of the glutamatergic synapses. The robust effect is expected to alter synapse function and plasticity and the cortico-hippocampal circuitry.
authors.affiliation: Department of Physiology and Cellular Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Chava
authors.initials: C
authors.lastname: Zuckerman
authors.affiliation: Department of Physiology and Cellular Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Elinor
authors.initials: E
authors.lastname: Blumkin
authors.affiliation: Department of Physiology and Cellular Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Osnat
authors.initials: O
authors.lastname: Melamed
authors.affiliation: Department of Physiology and Cellular Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel. Electronic address: havag@bgu.ac.il.
authors.forename: Hava M
authors.initials: HM
authors.lastname: Golan
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity; D001007:Anxiety / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D005838:Genotype; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011897:Random Allocation; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D020888:Vigabatrin / Q000633:toxicity*
chemical_list: D000927:Anticonvulsants; D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D000091042:Reelin Protein; D018698:Glutamic Acid; C000609029:MTHFR protein, mouse; D042965:Methylenetetrahydrofolate Reductase (NADPH2); C000717128:Reln protein, mouse; D012697:Serine Endopeptidases; D020888:Vigabatrin
keywords: AMPA R; Anxiety; GABA; NMDA R