title: Glycine N-methyltransferase expression in the hippocampus and its role in neurogenesis and cognitive performance.
abstract: The hippocampus is a brain area characterized by its high plasticity, observed at all levels of organization: molecular, synaptic, and cellular, the latter referring to the capacity of neural precursors within the hippocampus to give rise to new neurons throughout life. Recent findings suggest that promoter methylation is a plastic process subjected to regulation, and this plasticity seems to be particularly important for hippocampal neurogenesis. We have detected the enzyme GNMT (a liver metabolic enzyme) in the hippocampus. GNMT regulates intracellular levels of SAMe, which is a universal methyl donor implied in almost all methylation reactions and, thus, of prime importance for DNA methylation. In addition, we show that deficiency of this enzyme in mice (Gnmt-/-) results in high SAMe levels within the hippocampus, reduced neurogenic capacity, and spatial learning and memory impairment. In vitro, SAMe inhibited neural precursor cell division in a concentration-dependent manner, but only when proliferation signals were triggered by bFGF. Indeed, SAMe inhibited the bFGF-stimulated MAP kinase signaling cascade, resulting in decreased cyclin E expression. These results suggest that alterations in the concentration of SAMe impair neurogenesis and contribute to cognitive decline.
authors.affiliation: Area de Fisiologia, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Carrasco
authors.forename: Luis G
authors.initials: LG
authors.lastname: Rabaneda
authors.forename: Maribel
authors.initials: M
authors.lastname: Murillo-Carretero
authors.forename: Sylvia
authors.initials: S
authors.lastname: Ortega-Martínez
authors.forename: María L
authors.initials: ML
authors.lastname: Martínez-Chantar
authors.forename: Ashwin
authors.initials: A
authors.lastname: Woodhoo
authors.forename: Zigmund
authors.initials: Z
authors.lastname: Luka
authors.forename: Conrad
authors.initials: C
authors.lastname: Wagner
authors.forename: Shelly C
authors.initials: SC
authors.lastname: Lu
authors.forename: José M
authors.initials: JM
authors.lastname: Mato
authors.forename: Juan A
authors.initials: JA
authors.lastname: Micó
authors.forename: Carmen
authors.initials: C
authors.lastname: Castro
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000523:psychology*; D000818:Animals; D003071:Cognition / Q000502:physiology*; D019927:Cyclin E / Q000096:biosynthesis / Q000235:genetics; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D050938:Glycine N-Methyltransferase / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D006624:Hippocampus / Q000201:enzymology* / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000201:enzymology / Q000209:etiology; D008715:Methionine / Q000378:metabolism; D008716:Methionine Adenosyltransferase / Q000172:deficiency / Q000235:genetics; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D055495:Neurogenesis / Q000502:physiology*; D009473:Neuronal Plasticity; D045442:Rotarod Performance Test; D012436:S-Adenosylmethionine / Q000096:biosynthesis / Q000502:physiology*
chemical_list: D019927:Cyclin E; D009419:Nerve Tissue Proteins; D016222:Fibroblast Growth Factor 2; D012436:S-Adenosylmethionine; D008715:Methionine; D050938:Glycine N-Methyltransferase; C494511:Gnmt protein, mouse; C490703:Mat1a protein, mouse; D008716:Methionine Adenosyltransferase
keywords: S-adenosylmethionine; glycine N-methyltransferase; learning; memory; neural progenitor cells; neurogenesis