Deletion of SHATI/NAT8L decreases the N-acetylaspartate content in the brain and induces behavioral deficits, which can be ameliorated by administering N-acetylaspartate

Kazuya Toriumi, Takayoshi Mamiya, Ziyu Song, Tatsuki Honjo, Hiroyuki Watanabe, Junko Tanaka, Mizuki Kondo, Akihiro Mouri, Hyoung Chun Kim, Atsumi Nitta, Takeshi Fukushima, Toshitaka Nabeshima

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)2108-2117
Number of pages10
JournalEuropean Neuropsychopharmacology
Volume25
Issue number11
DOIs
Publication statusPublished - 01-11-2015
Externally publishedYes

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Brain
Methamphetamine
Nucleus Accumbens
Dopamine
aspartate N-acetyltransferase
N-acetylaspartate
Fluorescence
High Pressure Liquid Chromatography

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Neurology
  • Clinical Neurology
  • Psychiatry and Mental health
  • Biological Psychiatry
  • Pharmacology (medical)

Cite this

Toriumi, Kazuya ; Mamiya, Takayoshi ; Song, Ziyu ; Honjo, Tatsuki ; Watanabe, Hiroyuki ; Tanaka, Junko ; Kondo, Mizuki ; Mouri, Akihiro ; Kim, Hyoung Chun ; Nitta, Atsumi ; Fukushima, Takeshi ; Nabeshima, Toshitaka. / Deletion of SHATI/NAT8L decreases the N-acetylaspartate content in the brain and induces behavioral deficits, which can be ameliorated by administering N-acetylaspartate. In: European Neuropsychopharmacology. 2015 ; Vol. 25, No. 11. pp. 2108-2117.
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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.",
author = "Kazuya Toriumi and Takayoshi Mamiya and Ziyu Song and Tatsuki Honjo and Hiroyuki Watanabe and Junko Tanaka and Mizuki Kondo and Akihiro Mouri and Kim, {Hyoung Chun} and Atsumi Nitta and Takeshi Fukushima and Toshitaka Nabeshima",
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Deletion of SHATI/NAT8L decreases the N-acetylaspartate content in the brain and induces behavioral deficits, which can be ameliorated by administering N-acetylaspartate. / Toriumi, Kazuya; Mamiya, Takayoshi; Song, Ziyu; Honjo, Tatsuki; Watanabe, Hiroyuki; Tanaka, Junko; Kondo, Mizuki; Mouri, Akihiro; Kim, Hyoung Chun; Nitta, Atsumi; Fukushima, Takeshi; Nabeshima, Toshitaka.

In: European Neuropsychopharmacology, Vol. 25, No. 11, 01.11.2015, p. 2108-2117.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Deletion of SHATI/NAT8L decreases the N-acetylaspartate content in the brain and induces behavioral deficits, which can be ameliorated by administering N-acetylaspartate

AU - Toriumi, Kazuya

AU - Mamiya, Takayoshi

AU - Song, Ziyu

AU - Honjo, Tatsuki

AU - Watanabe, Hiroyuki

AU - Tanaka, Junko

AU - Kondo, Mizuki

AU - Mouri, Akihiro

AU - Kim, Hyoung Chun

AU - Nitta, Atsumi

AU - Fukushima, Takeshi

AU - Nabeshima, Toshitaka

PY - 2015/11/1

Y1 - 2015/11/1

N2 - 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.

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