Characterization of the neuropsychological phenotype of glycine N-methyltransferase-/- mice and evaluation of its responses to clozapine and sarcosine treatments

Ching Ping Yang, Hsiang An Wang, Tung Hu Tsai, Angela Fan, Chia Lang Hsu, Chun Jung Chen, Chen Jee Hong, Yi Ming Arthur Chen

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Glycine N-methyltransferase (GNMT) affects cellular methylation capacity through regulating the ratio between S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH). The product of its enzymatic reaction-sarcosine has antipsychotic effect in patients with schizophrenia. In this study, through RT-PCR and immunohistochemical staining, we demonstrated that GNMT expressed in various neurons located in the cerebral cortex, hippocampus, substantia nigra and cerebellum. Compared to the wild-type mice, Gnmt-/- mice had significantly lower level of sarcosine in the cerebral cortex. Real-time PCR identified genes involved in the methionine metabolism (Dnmt1 and Dnmt3a), ErbB (Nrg1 and ErbB4) and mTOR (Akt2, S6, S6k1 and S6k2) signaling pathways were dysregulated significantly in the cortex of Gnmt-/- mice. Acoustic startle reflex test demonstrated that Gnmt-/- mice had significantly lower level of prepulse inhibition and the deficit was ameliorated through clozapine or sarcosine treatment. Furthermore, liver-specific-human-GNMT transgenic with Gnmt-/- (Tg-GNMT/Gnmt-/-) mice were used to rule out that the phenotype was due to abnormal liver function. In summary, the neuropsychological abnormalities found in Gnmt-/- mice may represent an endophenotype of schizophrenia. GNMT plays an important role in maintaining normal physiological function of brain and Tg-GNMT/Gnmt-/- mice are useful models for development of therapeutics for patients with schizophrenia.

Original languageEnglish
Pages (from-to)596-606
Number of pages11
JournalEuropean Neuropsychopharmacology
Volume22
Issue number8
DOIs
Publication statusPublished - Aug 1 2012
Externally publishedYes

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Glycine N-Methyltransferase
Sarcosine
Clozapine
Phenotype
Schizophrenia
Cerebral Cortex
Therapeutics
Startle Reflex
S-Adenosylhomocysteine
Endophenotypes
S 6
S-Adenosylmethionine
Liver
Substantia Nigra
Methionine
Cerebellum
Methylation
Antipsychotic Agents
Real-Time Polymerase Chain Reaction
Hippocampus

Keywords

  • Endophenotype
  • Glycine N-methyltransferase
  • Knockout mice
  • Prepulse inhibition
  • Sarcosine
  • Schizophrenia

ASJC Scopus subject areas

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

Cite this

Characterization of the neuropsychological phenotype of glycine N-methyltransferase-/- mice and evaluation of its responses to clozapine and sarcosine treatments. / Yang, Ching Ping; Wang, Hsiang An; Tsai, Tung Hu; Fan, Angela; Hsu, Chia Lang; Chen, Chun Jung; Hong, Chen Jee; Chen, Yi Ming Arthur.

In: European Neuropsychopharmacology, Vol. 22, No. 8, 01.08.2012, p. 596-606.

Research output: Contribution to journalArticle

Yang, Ching Ping ; Wang, Hsiang An ; Tsai, Tung Hu ; Fan, Angela ; Hsu, Chia Lang ; Chen, Chun Jung ; Hong, Chen Jee ; Chen, Yi Ming Arthur. / Characterization of the neuropsychological phenotype of glycine N-methyltransferase-/- mice and evaluation of its responses to clozapine and sarcosine treatments. In: European Neuropsychopharmacology. 2012 ; Vol. 22, No. 8. pp. 596-606.
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AU - Hong, Chen Jee

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