The numbers of astrocytes in the human brain are higher than neurons. Although the existence of the cell within the brain tissue was found almost the same period as that of neurons, their roles in the brain have been thought only supporters for neurons. The functions as the blood-brain barrier, uptake of transmitters released from neurons and the energy supplies to neurons are important for maintaining brain function. Since astrocytes had been recognized as inert cells by electrophysiologists, they were treated as outsiders of the brain which worked as dynamic information-processing machinery using electricity. However, the end of 20^th century, unexpected function of astrocyte was found by Ca²⁺ fluorometry. Astrocytes were found to express almost all kinds of neurotransmitter receptors, which were mostly G-protein coupled type, and responded to many kinds of neurotransmitters by dynamic Ca²⁺ oscillation. Furthermore, the astrocytes were found to be able to activate neurons by substances released by themselves such as glutamate, ATP and D-serine, which are called “gliotransmitters” . Astrocytes are no longer supporting players for the brain, but the cells would participate in the neuronal circuit forming tripartite-synapse, and play important roles in higher-order brain functions.

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Psychiatric diseases are brain diseases and in many cases they are associated with the abnormality in the neuron or neuronal circuit. Recently, however, glial cells have been shown to play important roles in exerting higher brain functions and thus it is possible that defects in glial function to result in the abnormal brain function, resulting in the development of psychiatric diseases. Here I focus on the oligodendrocyte, the myelin forming cells of the central nervous system. Myelinated fibers form the brain white matter, which has been thought to be merely a pathway between the neurons, residing in the grey matter. This scheme has been challenged by the findings that 1) oligodendrocytes regulate the conduction velocity even after myelination is completed 2) evidences are accumulating showing the connection between the white matter abnormality and psychiatric diseases. It is now inevitable to study the utility of demyelinating disease therapy on the treatment of psychiatric diseases. In this review I will discuss about the integration of information passing through different pathway in the white matter and its relationship to the development of psychiatric diseases.

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Microglia were discovered by Pio del Rio-Hortega in 1919, and its functional roles have been successfully clarified by recent development of various experimental techniques, such as microglial culture method and generation of microglia-specific anti-Iba1 antibody. Furthermore, real time imaging studies by using Iba1-EGFP transgenic mice contributed to find the new functions of ramified microglia observed in the normal brain such as modification of synaptic transmission. In pathological brain, however, activated microglia secret pro-inflammatory factors, migrate and phagocytose suggesting the cells are involved in the pathogenicity of various disorders in the central nervous systems. Moreover, it is recently noted that microglia are also involved in the pathophysiology of psychiatric disorders such as autism spectrum disorder. In this paper, we summarize microglial functions revealed so far and discuss the role of microglia in the higher brain functions.

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Glutamate is the major excitatory neurotransmitter and plays important roles in the physiology of the mammalian central nervous system. In spite of its importance as a neurotransmitter, too much glutamate is toxic to neurons. Removal of glutamate from the extracellular space is critical for keeping the extracellular glutamate concentration below toxic level, and is mediated by GLT1 (EAAT2) and GLAST (EAAT1) , which are primarily expressed by astrocytes. Rare loss-of-function variants and down-regulation of GLT1 and GLAST have been reported in psychiatric disorders. In this review, we demonstrate that various kinds of GLT1 and/or GLAST knockout mice recapitulate many aspects of the developmental defects and behavioral abnormalities seen in human patients with major mental illnesses including schizophrenia and depression.

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Despite the physiological significance and linkage to schizophrenia, little is known about the posttranslational regulation of a major glial glutamate transporter GLAST. GLAST abounds at perisynaptic membrane domains in Bergmann glia and interacts with submembranous cytoskeletal components including septins（polymerizing GTPases）, myosin-10, and CDC42EP4（CDC42 effector protein 4）whose roles had been unknown. In Cdc42ep4^-/- mice, GLAST is dissociated from septins, and delocalized away from synaptic active zones. Electrophysiological analysis of the prarallel fiber-Purkinje cell synapses revealed protracted decay time constant in the excitatory postsynaptic current, and excessive baseline inward current in response to a subthreshold dose of a nonselective inhibitor of the glutamate transporters. The insufficient glutamate-buffering/clearance capacity in these mice manifested as motor coordination/learning defects, which were aggravated with the inhibitor at a subthreshold dose. These findings indicate that the CDC42EP4/septin-based glial scaffold facilitates perisynaptic localization of GLAST and optimizes the efficiency of glutamate-buffering and clearance. Given the accumulation and/or upregulation of several septin subunits and CDC42EP4 in dorsolateral prefrontal cortex in postmortem brains with schizophrenia and bipolar disorders, the resulting glutamate dysregulation may modulate pathophysiology of the psychiatric disorders.

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Despite recent advances in neuroscience, fundamental cause of schizophrenia still remains unknown and, thus far, our only effective antipsychotic drugs (dopamine antagonists) that rarely reach to complete remission are still based on the classical dopamine hypothesis. Thus, we need a novel hypothesis and translatable biomarker that enables early diagnosis, intervention and complete remission. Recent evidences show that abnormality in gamma-band (30-100 Hz) oscillations which relates to perception and cognition, exhibit neuronal deficits in schizophrenia. Impairments in gamma-band oscillation have been hypothesized to cause from disruptions of GABAergic inhibitory interneuron one act as a pacemaker in neural circuit, and excitatory neuron (NMDAR hypofunction) , as well as aberrant neuronal balance of excitation and inhibition (E/I balance) or disruptions in these tunings. Moreover, gamma-band oscillation deficit has attracted a lot of attention as a new pathophysiological model of schizophrenia and its therapeutic target since these phenomena can be obtained from animal models of schizophrenia. This presentation will review recent findings of gamma-band oscillation deficits in schizophrenia and illustrate its clinical usefulness as a novel translatable biomarker that give rise to critical features of neural dysfunction associated with schizophrenia.

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Accumulating evidence suggests a key role of the N-methyl-D-aspartate (NMDA) receptor in the pathophysiology of post-traumatic stress disorder (PTSD) . Recent studies suggest that the NMDA receptor antagonist ifenprodil tartrate may be a potential therapeutic drug for PTSD. The purpose of this study is to confirm whether ifenprodil tartrate is effective in the treatment of adolescents (13-18 years old) PTSD patients. If ifenprodil tartrate is effective in these patients, this study contributes to the development of novel therapeutic drugs for PTSD. This study is an interventional, randomized, parallel assignment, double blinded clinical trial. The primary outcome measure is Impact of Event Scale-Revised Japanese Version: IES-R-J and the secondary outcome measure are Trauma Symptom Checklist for Children Japanese Version: TSCC-J, Children’s Depression Rating Scale-Revised: CDRS-R, Depression Self-Rating Scale for Children Japanese Version: DSRS-C-J and CGI-scores. [Time Frame: Changes from baseline in these scores at 4-weeks]

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