Cognitive Impairment Is Associated with AMPAR Glutamatergic Dysfunction in a Mouse Model of Neuronal Methionine Synthase Deficiency

• Published in: Cells (Basel, Switzerland) Vol. 12; no. 9; p. 1267
• Main Authors: Hassan, Ziad, Coelho, David, Bossenmeyer-Pourié, Carine, Matmat, Karim, Arnold, Carole, Savladori, Aurélie, Alberto, Jean-Marc, Umoret, Rémy, Guéant, Jean-Louis, Pourié, Grégory
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 27-04-2023; MDPI
• Subjects: 5-Methyltetrahydrofolate-homocysteine S-methyltransferase; 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase - metabolism; Alzheimer's disease; Amino Acid Metabolism, Inborn Errors; Analysis; Animal models; Animals; Brain; Carbon; Care and treatment; Cognition disorders; Cognitive ability; Cognitive Dysfunction; Deficiency diseases; Diagnosis; Dietary supplements; Enzymes; Epigenetics; Excitability; Female; Functional plasticity; Gene expression; Glutamatergic transmission; Growth rate; Health aspects; inherited disorders; Investigations; Laboratory animals; Life Sciences; Males; Metabolism; Methionine; methionine synthase; Methylation; Mice; Neural plasticity; Neurodevelopmental disorders; neurologic dysfunction; Neurons and Cognition; Neurophysiology; Nitrogen; Nutrient deficiency; Phosphorylation; Pregnancy; Prevention; Proteins; Risk factors; Suckling behavior; Vitamin B; Vitamin B 12; Vitamin B12; vitamin B12 metabolism; Vitamin deficiency; Weaning; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors; France; United States > US; neurologic dysfunction; vitamin B12 metabolism; inherited disorders; methionine synthase
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells12091267

Impairment of one-carbon metabolism during pregnancy, either due to nutritional deficiencies in B9 or B12 vitamins or caused by specific genetic defects, is often associated with neurological defects, including cognitive dysfunction that persists even after vitamin supplementation. Animal nutritional models do not allow for conclusions regarding the specific brain mechanisms that may be modulated by systemic compensations. Using the Cre-lox system associated to the neuronal promoter Thy1.2, a knock-out model for the methionine synthase specifically in the brain was generated. Our results on the neurobehavioral development of offspring show that the absence of methionine synthase did not lead to growth retardation, despite an effective reduction of both its expression and the methylation status in brain tissues. Behaviors were differently affected according to their functional outcome. Only temporary retardations were recorded in the acquisition of vegetative functions during the suckling period, compared to a dramatic reduction in cognitive performance after weaning. Investigation of the glutamatergic synapses in cognitive areas showed a reduction of AMPA receptors phosphorylation and clustering, indicating an epigenomic effect of the neuronal deficiency of methionine synthase on the reduction of glutamatergic synapses excitability. Altogether, our data indicate that cognitive impairment associated with methionine synthase deficiency may not only result from neurodevelopmental abnormalities, but may also be the consequence of alterations in functional plasticity of the brain.