title: Do reductions in brain N-acetylaspartate levels contribute to the etiology of some neuropsychiatric disorders?
abstract: N-acetylaspartate (NAA) is recognized as a noninvasive diagnostic neuronal marker for a host of neuropsychiatric disorders using magnetic resonance spectroscopy (MRS). Numerous correlative clinical studies have found significant decreases in NAA levels in specific neuronal systems in an array of neuropsychiatric and substance-abuse disorders. We have recently identified the methamphetamine-induced neuronal protein known as "shati" as the NAA biosynthetic enzyme (aspartate N-acetyltransferase [Asp-NAT]; gene Nat8l). We have generated an Nat8l transgenic knockout mouse line to study the functions of NAA in the nervous system. We were unable to breed homozygous Nat8l knockout mice successfully for study and so used the heterozygous mice (Nat8l(+/-) ) for initial characterization. MRS analysis of the Nat8l(+/-) mice indicated significant reductions in NAA in cortex (-38%) and hypothalamus (-29%) compared with wild-type controls, which was confirmed using HPLC (-29% in forebrain). The level of the neuromodulator N-acetylaspartylglutamate (NAAG), which is synthesized from NAA, was decreased by 12% in forebrain as shown by HPLC. Behavioral analyses of the heterozygous animals indicated normal behavior in most respects but reduced vertical activity in open-field tests compared with age- and sex-matched wild-type mice of the same strain. Nat8l(+/-) mice also showed atypical locomotor responses to methamphetamine administration, suggesting that NAA is involved in modulating the hyperactivity effect of methamphetamine. These observations add to accumulating evidence suggesting that NAA has specific regulatory functional roles in mesolimbic and prefrontal neuronal pathways either directly or indirectly through impact on NAAG synthesis
authors: Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, USA.
authors: Prasanth S
authors: PS
authors: Ariyannur
authors: Peethambaran
authors: P
authors: Arun
authors: Erin S
authors: ES
authors: Barry
authors: Brian
authors: B
authors: Andrews-Shigaki
authors: Asamoah
authors: A
authors: Bosomtwi
authors: Haiying
authors: H
authors: Tang
authors: Reed
authors: R
authors: Selwyn
authors: Neil E
authors: NE
authors: Grunberg
authors: John R
authors: JR
authors: Moffett
authors: Aryan M A
authors: AM
authors: Namboodiri
mesh_terms: D000123:Acetyltransferases / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002794:Choline / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004151:Dipeptides / Q000172:deficiency / Q000235:genetics; D015259:Dopamine Agents / Q000494:pharmacology; D005106:Exploratory Behavior / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D008124:Locomotion / Q000187:drug effects / Q000235:genetics; D009682:Magnetic Resonance Spectroscopy; D008694:Methamphetamine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D004151:Dipeptides; D015259:Dopamine Agents; C027172:isospaglumic acid; D001224:Aspartic Acid; D008694:Methamphetamine; C000179:N-acetylaspartate; D000123:Acetyltransferases; C046791:aspartate N-acetyltransferase; D002794:Choline