title: Mouse model for deficiency of methionine synthase reductase exhibits short-term memory impairment and disturbances in brain choline metabolism.
abstract: Hyperhomocysteinaemia can contribute to cognitive impairment and brain atrophy. MTRR (methionine synthase reductase) activates methionine synthase, which catalyses homocysteine remethylation to methionine. Severe MTRR deficiency results in homocystinuria with cognitive and motor impairments. An MTRR polymorphism may influence homocysteine levels and reproductive outcomes. The goal of the present study was to determine whether mild hyperhomocysteinaemia affects neurological function in a mouse model with Mtrr deficiency. Mtrr+/+, Mtrr+/gt and Mtrrgt/gt mice (3 months old) were assessed for short-term memory, brain volumes and hippocampal morphology. We also measured DNA methylation, apoptosis, neurogenesis, choline metabolites and expression of ChAT (choline acetyltransferase) and AChE (acetylcholinesterase) in the hippocampus. Mtrrgt/gt mice exhibited short-term memory impairment on two tasks. They had global DNA hypomethylation and decreased choline, betaine and acetylcholine levels. Expression of ChAT and AChE was increased and decreased respectively. At 3 weeks of age, they showed increased neurogenesis. In the cerebellum, mutant mice had DNA hypomethylation, decreased choline and increased expression of ChAT. Our work demonstrates that mild hyperhomocysteinaemia is associated with memory impairment. We propose a mechanism whereby a deficiency in methionine synthesis leads to hypomethylation and compensatory disturbances in choline metabolism in the hippocampus. This disturbance affects the levels of acetylcholine, a critical neurotransmitter in learning and memory.
authors.affiliation: *Departments of Human Genetics and Pediatrics, McGill University, Montreal Children's Hospital site of the McGill University Health Centre Research Institute, 4060 Ste. Catherine St. West, Montreal, Quebec, Canada, H3Z 2Z3.
authors.forename: Nafisa M
authors.initials: NM
authors.lastname: Jadavji
authors.affiliation: *Departments of Human Genetics and Pediatrics, McGill University, Montreal Children's Hospital site of the McGill University Health Centre Research Institute, 4060 Ste. Catherine St. West, Montreal, Quebec, Canada, H3Z 2Z3.
authors.forename: Renata H
authors.initials: RH
authors.lastname: Bahous
authors.affiliation: *Departments of Human Genetics and Pediatrics, McGill University, Montreal Children's Hospital site of the McGill University Health Centre Research Institute, 4060 Ste. Catherine St. West, Montreal, Quebec, Canada, H3Z 2Z3.
authors.forename: Liyuan
authors.initials: L
authors.lastname: Deng
authors.affiliation: †Division of Nutritional Sciences, Cornell University, 241 Kinzelberg Hall, Ithaca, NY 14853 6300, U.S.A.
authors.forename: Olga
authors.initials: O
authors.lastname: Malysheva
authors.affiliation: ‡Department of Neurology and Neurosurgery, McGill University, Montreal Neurological Institute, 3801 University Street, Montreal, Quebec, Canada, H3A 2B4.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Grand'maison
authors.affiliation: ‡Department of Neurology and Neurosurgery, McGill University, Montreal Neurological Institute, 3801 University Street, Montreal, Quebec, Canada, H3A 2B4.
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Bedell
authors.affiliation: †Division of Nutritional Sciences, Cornell University, 241 Kinzelberg Hall, Ithaca, NY 14853 6300, U.S.A.
authors.forename: Marie A
authors.initials: MA
authors.lastname: Caudill
authors.affiliation: *Departments of Human Genetics and Pediatrics, McGill University, Montreal Children's Hospital site of the McGill University Health Centre Research Institute, 4060 Ste. Catherine St. West, Montreal, Quebec, Canada, H3Z 2Z3.
authors.forename: Rima
authors.initials: R
authors.lastname: Rozen
mesh_terms: D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001622:Betaine / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism* / Q000473:pathology; D002794:Choline / Q000378:metabolism; D002795:Choline O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004195:Disease Models, Animal; D005287:Ferredoxin-NADP Reductase / Q000172:deficiency / Q000235:genetics*; D015870:Gene Expression; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006710:Homocysteine / Q000378:metabolism; D006712:Homocystinuria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020138:Hyperhomocysteinemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008570:Memory, Short-Term; D008715:Methionine / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009435:Synaptic Transmission
chemical_list: D006710:Homocysteine; D001622:Betaine; D008715:Methionine; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase; D002794:Choline