Induced pluripotent stem cells (iPSCs) are derived through reprogramming somatic cells into a pluripotent embryonic stem cell (ESC)-like state. Generated iPSCs are capable to differentiate into various cell types including neuronal cells. The disease modeling using patient iPSC-derived neuronal cells would elucidate disease pathogenesis and contribute to drug discovery for neurodegenerative diseases. We report our recent progress toward understanding of neurodegenerative diseases using iPSC technology.

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It has now been widely accepted as “Glutamate Hypothesis of Schizophrenia” that disturbed neurotransmission via the N-methyl-D-aspartate type glutamate receptor may be implicated in the pathophysiology of schizophrenia, because (1) competitive and non-competitive antagonists of the NMDA receptor cause schizophrenia-like positive and negative symptomatologies, (2) the rank order potency of schizophrennomimetic effects of NMDA receptor antagonists is closely correlated with that of their NMDA receptor-current blocking efficacies, and (3) schizophrenic patients have been reported to be more sensitive to psychotomimetic actions of NMDA antagonists than healthy volunteers. The fact that selective elimination of endogenous D-serine attenuates NMDA receptor functions in mammalian brains suggests that dysregulation of the extracellular contents of D-serine could be a candidate mechanism for the possible NMDA receptor dysfunction. The induction of current pharmacotherapy-resistant symptoms by NMDA receptor antagonists leads to the idea that NMDA receptor-D-serine system could be a suitable target for further analysis of the pathophysiology and development of novel pharmacotherapy for schizophrenia. Therefore, in this article, we are trying to overview the present status of understanding of the molecular and cellular mechanisms underlying release and uptake of D-serine and their controls. Future applications of these findings to drug discovery for intractable schizophrenic symptoms are also discussed.

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The N-methyl-D-aspartic acid (NMDA) hypofunction model of schizophrenia is based on the ability of NMDA receptor antagonists to mimic schizophrenic symptoms. Glutamate system and gamma- amino butyric acid (GABA) system have functional correlation. NMDA receptor hypofunction on GABAergic neuron could cause hypofunction of GABA system, and may lead to disinhibition of pyramidal neurons, cortical excitation and neural toxity. The proton magnetic resonance spectroscopy (1H-MRS) technique can evaluate the metabolites levels in the region of interest of brain. Recently, new techniques of MRS become available which allow separated determination of glutamate, glutamine and GABA from its close spectral position. The aim of this article is to provide an overview of existing MRS studies which support the NMDA hypofunction model of schizophrenia.

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The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine is reported to show rapid antidepressant effects in treatment-resistant patients with major depression and bipolar depression. Therefore, the NMDA receptor is one of the most attractive therapeutic targets for depression. At present, the novel therapeutic drugs for depression have been developing. Here the author would like to discuss the role of glutamate in the pathophysiology of depression and the possibility of NMDA receptor as a therapeutic target.

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Abnormalities in L-glutamate signal transmission have been postulated to play a role in major mental illnesses. The glial disruption results in decreased uptake of glutamate and an elevation of extracellular glutamate levels. Elevated extracellular glutamate may cause cytotoxic damage to neurons and glia. Rare variants and down-regulation of glial glutamate transporters, GLT1 and GLAST, in psychiatric disorders has been reported. In the present study we examined the role of glial glutamate transporters in the pathogenesis of major metal illnesses including schizophrenia, depression, obsessive -compulsive disorders and autism. We generated animal models in which glutamate receptors are overstimulated by genetic down-regulation of glial glutamate transporters. Resulting mutant mice showed abnormal social interaction, increased anxiety-like behavior, physical tics and compulsive grooming behavior and select phenotypic abnormalities related to the negative and cognitive symptoms of schizophrenia. These mutant mice replicate many aspects of the behavioral and neuroanatomical abnormalities seen in major mental illnesses. Thus, these mutants are new animal models of major mental illness. Therefore, augmentation of glial glutamate transporter activity may be a novel strategy for the management of major mental illnesses.

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The hypothesis that GABA and GABAergic transmission are involved in the pathophysiology of schizophrenia has been one of the representative ideas. Studies of postmortem brain found alterations in the expression of GABAergic transmission-related genes and in particular, reduced expression of a GABA-synthesizing enzyme, glutamate decarboxylase 67 (GAD67). Because of the limitations of the experimental approach in human, it is important to characterize animal models to validate the GABA hypothesis of schizophrenia. Here, we review several animal models for schizophrenia showing both behavioral abnormalities and downregulation of GAD67 expression. The disturbance in GAD67 expression could represent a common molecular pathophysiology for dysfunctions in schizophrenia. We also review the use for GAD67-GFP knock- in mice that have been applied to characterization of psychiatric disease model mice with GABAergic deficit such as disturbance of GABAergic neuron migration, based on the fact that GFP is specifically expressed in GABAergic neurons in these knock- in mice. Establishment of another model animal with GABAergic dysregulation or genetically engineered rodents in GABAergic transmission- related genes will provide an opportunity to further understand the pathogenesis of schizophrenia.

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