Do reductions in brain N-acetylaspartate levels contribute to the etiology of some neuropsychiatric disorders?

Prasanth S. Ariyannur, Peethambaran Arun, Erin S. Barry, Brian Andrews-Shigaki, Asamoah Bosomtwi, Haiying Tang, Reed Selwyn, Neil E. Grunberg, John R. Moffett, Aryan M.A. Namboodiri

Research output: Contribution to journalArticle

10 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)934-942
Number of pages9
JournalJournal of Neuroscience Research
Volume91
Issue number7
DOIs
StatePublished - Jul 1 2013
Externally publishedYes

Keywords

  • Dopamine
  • HPLC
  • Locomotor activity
  • Magnetic resonance spectroscopy
  • Methamphetamine
  • N-acetylaspartylglutamate
  • NAA
  • NAAG

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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  • Cite this

    Ariyannur, P. S., Arun, P., Barry, E. S., Andrews-Shigaki, B., Bosomtwi, A., Tang, H., Selwyn, R., Grunberg, N. E., Moffett, J. R., & Namboodiri, A. M. A. (2013). Do reductions in brain N-acetylaspartate levels contribute to the etiology of some neuropsychiatric disorders? Journal of Neuroscience Research, 91(7), 934-942. https://doi.org/10.1002/jnr.23234