title: Deletion of SHATI/NAT8L decreases the N-acetylaspartate content in the brain and induces behavioral deficits, which can be ameliorated by administering N-acetylaspartate.
abstract: We previously identified a novel molecule "SHATI/NAT8L" that exerts an inhibitory effect on methamphetamine (METH)-induced behavioral deficits. Recently, it has been reported that SHATI might function as an aspartate N-acetyltransferase, which synthesizes N-acetylaspartate (NAA) in vitro. However, whether SHATI actually synthesizes NAA in vivo in the brain is still unclear. In this study, we found that both Shati-deleted mice showed significantly lower NAA levels in all brain areas than wild-type (Shati(+/+)) mice using HPLC and fluorescence detection, suggesting that SHATI regulates NAA content in the brain. Next, we measured the levels of monoamines and their metabolites in the adult mouse brain and found that the activities of monoaminergic systems were altered in Shati(-/-) mice. In particular, dopaminergic turnover increased in the nucleus accumbens (NAc) in Shati(-/-) mice, suggesting activation of the dopaminergic system. In fact, basal level of extracellular dopamine, and METH-induced dopamine release in the NAc of Shati(-/-) mice was significantly higher than that of Shati(+/+) and Shati(+/-) mice, which is consistent with findings that Shati(-/-) mice showed enhanced hyperlocomotion induced by METH. Moreover, in the forced swimming test, Shati-deleted mice showed a shortened immobility time, which was improved by intracerebroventricular (i.c.v.) administration of NAA prior to the test in Shati(+/-) but not in Shati(-/-) mice. The i.c.v. preinjection of NAA inhibited dopamine release after high K(+) stimulation in the NAc of Shati(+/+) and Shati(+/-) mice, but not Shati(-/-) mice. These results suggested that the behavioral deficits in Shati-deleted mice were caused by dopaminergic abnormality via deprivation of NAA.
authors.affiliation: Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan; Project for Schizophrenia Research, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Toriumi
authors.affiliation: Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan; Japanese Drug Organization of Appropriate Use and Research, Nagoya, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Mamiya
authors.affiliation: Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences, Toho University, Chiba, Japan.
authors.forename: Ziyu
authors.initials: Z
authors.lastname: Song
authors.affiliation: Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan.
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Honjo
authors.affiliation: Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Tanaka
authors.affiliation: Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Kondo
authors.affiliation: Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan; Division of Clinical Sciences and Neuropsychopharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan; Japanese Drug Organization of Appropriate Use and Research, Nagoya, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Mouri
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Korea Institute of Drug Abuse, Chunchon, South Korea.
authors.forename: Hyoung-Chun
authors.initials: HC
authors.lastname: Kim
authors.affiliation: Department of Pharmaceutical Therapy & Neuropharmacology, Faculty of Pharmaceutical Science, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, Toyama, Japan; Japanese Drug Organization of Appropriate Use and Research, Nagoya, Japan.
authors.forename: Atsumi
authors.initials: A
authors.lastname: Nitta
authors.affiliation: Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences, Toho University, Chiba, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Fukushima
authors.affiliation: Nabeshima Laboratory, Faculty of Pharmacy, Meijo University, Nagoya, Japan; Japanese Drug Organization of Appropriate Use and Research, Nagoya, Japan. Electronic address: tnabeshi@ccalumni.meijo-u.ac.jp.
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nabeshima
mesh_terms: D000123:Acetyltransferases / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D001224:Aspartic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D015306:Biogenic Monoamines / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002491:Central Nervous System Agents / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D008694:Methamphetamine / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011897:Random Allocation; D012919:Social Behavior
chemical_list: D015306:Biogenic Monoamines; D002491:Central Nervous System Agents; D001224:Aspartic Acid; D008694:Methamphetamine; C000179:N-acetylaspartate; D000123:Acetyltransferases; C521704:Shati protein, mouse
keywords: Dopamine; Monoamine; N-acetyl aspartate; SHATI