Characterization of the Neuropsychological Phenotype of Glycine N-Methyltransferase knockout mice

• Main Authors: Ching-Ping Yang, 楊境評
• Other Authors: Yi-Ming Arthur Chen
• Format: Others
• Language: en_US
• Published: 2012
• Online Access: http://ndltd.ncl.edu.tw/handle/78663900855124106142

博士 === 國立陽明大學 === 公共衛生研究所 === 100 === Abstract Schizophrenia is a common psychiatric disorder with a prevalence of approximately 1 % in the general population worldwide and is characterized by psychotic symptoms such as hallucinations, delusions and cognitive deficits. Twin studies have confirmed that schizophrenia is highly genetically influenced, but the genetics have proven to be markedly complex, with risk resulting from the interplay of diverse genetic variants with stochastic and environmental factors. Besides dopaminergic neurotransmission, glutamatergic neurotransmission via NMDA receptors has been implicated in the pathophysiology of schizophrenia. Recently, several studies showed that the glycine transporter I inhibitor N-methylglycine (sarcosine) improved not only psychotic but also depressive symptoms in patients with schizophrenia. Glycine N-methyltransferase (GNMT) has multiple functions. It is a folate binding protein and regulates the ratio of S-adenosylmethionine to S-adenosylhomocysteine by catalyzing sarcosine synthesis from glycine. The objectives of this project were 1.) to study the tissue distribution of GNMT in the mouse brain, 2.) to elucidate the molecular mechanisms involved in Gnmt-/- mice and 3.) to characterize behavioral changes in Gnmt-/-mice. In addition, we demonstrated that both clozapine and sarcosine can rescue prepulse inhibition (PPI) deficits in Gnmt-/- mice. In this study, through RT-PCR and immunohistochemical staining, we demonstrated that GNMT expressed in neurons located in the cortex, hippocampus, substantia nigra and cerebellum. Compared to wild-type mice, Gnmt-/- mice had significantly lower level of sarcosine in the cerebral cortex. In addition, we identified genes involved in methionine metabolism by microarray and real-time PCR, and ErbB and mTOR signaling pathways were found to be significantly dysregulated in the cortex of male Gnmt-/- mice. The acoustic startle reflex inhibition test demonstrated that male Gnmt-/- mice had significantly lower level of prepulse inhibition and the deficit was ameliorated through clozapine and sarcosine treatment. Furthermore, human GNMT liver-specific transgenic mice mated with Gnmt-/- (Tg-GNMT/Gnmt-/-) were generated and ruled out that the Gnmt-/- phenotypes observed were due to abnormal liver function. In summary, GNMT plays an important role in maintaining normal function of the brain and Tg-GNMT/Gnmt-/- mice are useful for screening glycine transporter I inhibitors.