The pathophysiology of schizophrenia (SZ) remains unknown despite the progress of neuroscience, which has hindered the invention of radical treatment of SZ. Various lines of evidence, including human genetics, suggest that the abnormality of synapses is involved in its pathophysiology, but none of them indicates its direct causality. The utility of model animal can be a plausible surrogate for the human disease, allowing researchers to pursue invasive and manipulative experiments. Therefore, we overview the evidence of synaptic pathology in the schizophrenia model animals. Furthermore, we introduce our new optical technique to visualize and manipulate synapses, which enables us to provide direct evidence of the involvement of synapses in the disease.

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Neurons make a neural network and communicate each other via their synapses. Synaptic accumulation of neurotransmitter receptors is necessary for efficient neurotransmission. A member of kinesin superfamily proteins (KIFs) KIF17 transports NMDA receptor subunit 2B in dendrites. KIF17 is essential for neuronal plasticity such as long‐term potentiation (LTP) and long‐term depression (LTD) in hippocampus. Lack of KIF17 resulted in memory disturbances in mice. Transport of NMDA receptors is regulated by phosphorylation and CREB‐mediated upregulation of motor and cargoes in an activity‐dependent manner. The transport of NMDA receptors was also supported by a non‐motor microtubule‐associated protein MAP1A. These multiple ways of regulation of NMDA‐receptor transport support neuronal plasticity and brain function such as learning and memory. Recently, lines of evidence from genetic and post‐mortem examination approaches indicate that compromised NMDA receptor function in schizophrenia might be linked to alteration in KIF17‐mediated transport of NMDA receptor. Further translational research is needed to elucidate the contribution of KIF17 to the pathogenesis and pathophysiology of schizophrenia.

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The basal ganglia are important neural substrates that control decision making and cognitive learning, and involve the pathophysiology of mental disorders. We have an interest in the role of ventral pallidum in the basal ganglia functions and dysfunctions, because left pallidum is enlarged in schizophrenic patients. We have demonstrated that specific stimulation of preproenkephalin‐positive neurons in the ventral pallidum impaired inhibitory avoidance learning, but not reward learning. We also showed that preproenkephalin mRNA is predominantly expressed in GABAergic neurons in the ventral pallidum. Further analyses of neural circuit mechanisms of the ventral pallidum in the pathophysiology of schizophrenia are required.

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Increased density of white matter neurons (WMNs) in the neocortex has been reported as one of the reproducible histological changes in postmortem brains from subpopulations of patients with schizophrenia and autistic spectrum disorder (ASD) . Although researchers have thought that the changes are caused by migration defects of the neocortical neurons or failed apoptosis of the subplate (SP) neurons, no discrete conclusions have been arrived at yet. If the increase in the density of the WMNs were caused by failed apoptosis of the SP neurons, alterations of the SP neurons might underlie the presumed abnormal cortical wiring in schizophrenic or ASD brains, since the SP plays a key role in the establishment of neocortical connectivity during development. On the other hand, recent experimental mouse studies have demonstrated that either genetic or environmental factors that enhance the risk of neuropsychiatric disorders during development could cause neuronal migration deficits and altered distribution of the neocortical neurons in the white matter. In our newly established experimental mouse models, abnormal neocortical wiring was observed when the number of neocortical WMNs was artificially increased. Further investigations of the brains of both human patients and animal models will contribute to a precise elucidation of the pathophysiological mechanisms underlying the increased density of the neocortical WMNs in the subpopulations of schizophrenia/ASD patients.

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Computational psychiatry is a new research field which seeks to understand mental disorders as aberrant computation by using mathematical modeling of information processing in the brain. Thanks to some exciting discoveries in computational neuroscience that addressed underlying neurobiology of cognitive function, expectations for the contributions of computational approach to psychiatric disorders have been increasing. In recent years, since use of mathematical models in the scientific research, such as machine learning, artificial intelligence and data science (big‐data) , has become popular, it has got easier to obtain cooperation for the studies of psychiatry from researchers with mathematical and theoretical backgrounds. However, that is especially, involvements of psychiatrist with clinical experiences and sophisticated expertise of psychiatric symptomatology and psychopathology are vital for the studies of computational psychiatry. In order to encourage involvements of young psychiatrists in computational psychiatry, I will introduce how a clinical psychiatrist without any experiences of basic research and mathematical/theoretical background has struggled with the studies of computational neuroscience/psychiatry, including neural network modeling of cognitive functions and robotic models of psychiatric disorders.

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While translational research in psychiatry and neuroscience is increasingly required, few psychiatrists are interested in basic research. In this article, we introduce life in the laboratory to psychiatrists who are interested in basic research. I wrote about the practical aspects of the laboratory, such as daily experiments, theme selection, life rhythms, and economics. I hope that it will be helpful for the selection of the future course of the junior.

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Neurodevelopmental hypothesis of psychiatric disorders, by definition, requires developmental understanding of psychiatric disorders. Human cerebral cortex, for example, has many areas that differ in their cytoarchitecture and function, and they have distinct pathophysiological significance in patients with psychiatric disorders. We know very little about areal differences in brain development, however. Deep understandings of how the whole brains are formed by diverse cells provide great opportunity to study possible local and global vulnerability of human brains. Investigating the causal relationship between this vulnerability and psychiatric disorders would lead us to the understanding of the pathogenesis. In summary, the advancement of the study on the pathogenesis of psychiatric disorders would require deep understanding of normal brain development.

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For psychiatrists interested in research, balancing time between research and clinical practice is challenging. Furthermore, this situation is made more difficult by the need to accommodate the demands of private life with maintaining professional competency. The MD Scientist Training Program (MDSTP) at The University of Tokyo gave the author a chance to consider career path. Currently, more than half of the graduates of MDSTP belong to a basic graduate school department. Understanding illness trajectory in clinical practice produces fruitful research ideas which in turn may contribute to improving clinical medicine. Experiencing different philosophies and ways of doing things can also broaden our perspective. The author entered graduate school after obtaining a board certificate and designated physician of mental health, namely expertise as an external standard. Since optimizing time allocation prospectively is challenging, psychiatrists should go through their residency guided by their own values or standards (through generating their own internal standard) . Most of the psychiatrists with whom the author is acquainted are happily walking the path of “their choice”. The author is grateful to be part of this diverse culture.

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