Neuropathological investigation is a classic technique that has conducted for over 100 years in the study of the pathophysiology of schizophrenia. The findings from neuropathological investigations have indicated abnormalities in neurodevelopment, such as neuronal differentiation, neuronal migration, neurite branching, neurite elongation and synapse formation in schizophrenia, and have contributed to the elucidation of the pathogenesis of schizophrenia. However, it has been often difficult to clarify whether the observational findings are due to the disease itself, as the findings may be affected by lifetime events, including agonal factors. In addition, reproducibility may also be affected by biological heterogeneity in schizophrenia diagnosed based on operational diagnostic criteria. Therefore, we focus on schizophrenia with rare variants as one of the strategies, and conducted neuropathological investigations with consideration of the genomic background in order to reveal more disease‐specific neuropathological findings. In order to elucidate the pathology of schizophrenia, it is desirable not only to accumulate postmortem brains, but also to expand brain banks that have genome analysis information.

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In evaluating the pathophysiology of neuropsychiatric disorders, it is helpful to take account of research on neurodegenerative diseases showing psychiatric symptoms, such as Alzheimer’s disease or dementia with Lewy bodies. Recent pathological studies have mostly focused on the neuronal circuits associated with psychiatric features, especially the mesolimbic dopaminergic pathway. For example, primary age‐related tauopathy, one of tauopathies characterized by pathological aggregation of tau protein, is known to present with delusions, and it has been suggested that increased levels of phosphorylated tau in the nucleus accumbens are associated with psychiatric symptoms. Furthermore, recent clinicopathological studies of monoaminergic systems indicate the association of nigrostriatal degeneration with depression across the Lewy body disease spectrum. Here, I review studies of age‐related pathologies linked to psychiatric symptoms, focusing on neuronal circuits, including our recent pathological studies of psychiatric disorders.

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Neuropathological classification of neurodegenerative diseases has been established based on proteinopathy, which indicates neuronal loss and gliosis associated with protein specific inclusions in the focal regions responsible for clinical signs and symptoms. Although the neuropathology of psychiatric disorders, such as schizophrenia and bipolar disorder still remain obscure, the organization of psychiatric Brain bank proceeds accumulation of brain tissue as research resources. The most important role of neuropathology in brain bank is to pronounce correct neuropathological diagnosis, because combination of various proteinopathies, such as Alzheimer’s disease and Parkinson’s disease, cerebrovascular disorders, trauma and ischemic changes in the terminal stages modify the pathological findings. Brain bank can verify again in the disease brain tissue according to recent advances in neuroimaging techniques, and molecular biological research.

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We are conducting 3D analysis of neurons in human brain tissue using synchrotron radiation computed tomography (CT) ; both nano‐CT and micro‐CT. Synchrotron radiation is generated by accelerating charged particles and used mainly as strong X‐rays. Application of the high‐brilliance X‐rays to the CT methodology allowed us to achieve a 3D resolution of approximately 10,000 times finer than that of the medical CT. We applied the nano‐CT to the analysis of postmortem brain tissue from schizophrenia and control cases and found that the curvature of neurites in schizophrenia is significantly correlated with the auditory hallucination score. These results indicate that schizophrenia is a psychiatric disorder with significant changes in neural structure . Studies of human brain tissue are essential to elucidate the pathophysiology of such disorders and thus the importance and necessity of brain banks will only increase more in the future. The latter half of this paper outlines the organization and operation of the Stanley Medical Research Institute Brain Bank, which is one of the main brain banks for schizophrenia and bipolar disorder in the U.S. We also summarize other current brain banks in the U.S. and their cooperation as a national resource.

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Piccolo, a presynaptic protein, plays a role in synaptic vesicle trafficking of neurotransmission process. Previous studies have revealed that the Piccolo‐coding gene PCLO were associated with psychiatric disorders. However, few studies are available on the causal relationship between Piccolo dysfunction and psychosis symptoms in vivo. Accordingly, phenotypes in mice with suppression of Piccolo in the medial prefrontal cortex (mPFC) were evaluated. Piccolo‐suppressed mice showed hyperlocomotion in a novel environment, impaired prepulse inhibition and decreased cognitive function. These behaviors were partially ameliorated by atypical antipsychotic drug. The mice exposed to mild social defeat stress exhibited additional social withdrawal and behavioral despair. Furthermore, synaptic plasticity in the mPFC and glutamatergic and dopaminergic neurotransmission by activating mPFC projection in the dorsal striatum were inhibited in Piccolo‐suppressed mice. These observations suggest that disconnection with the mPFC pathway via suppression of Piccolo mediates schizophrenia symptoms, e. g. positive and negative symptoms and cognitive deficit.

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In vitro neuronal differentiation from induced pluripotent stem (iPS) cells is a highly useful technology in neuronal disease research since it allows observation and manipulation of patient‐specific cells. However, there are still many challenges in disease modeling in vitro. One of the major reasons is that the technology for inducing subtype‐specific neuronal differentiation from iPS cells still needs to be improved. In this study, we introduce a research platform for pathophysiology of psychiatric disorders and drug screening by using gene transfer of bHLH (basic‐Helix‐Loop‐Helix) type transcription factors such as NEUROG2 and ASCL1, and discuss its usefulness and future challenges.

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Thanks to iPS cell technology, it is now possible to directly investigate neuronal dysfunction in vitro using neural cells that retain the patient’s genetic background. Considering the species differences in brain functions between humans and model organisms such as mice, molecular and cellular pathological research using human (patient) neurons is important, which is expected to complement conventional research. To date, many iPS cell‐differentiated neurons derived from patients with schizophrenia have been generated and analyzed for the molecular and cellular pathogenesis of the disease. Accordingly, promising candidates for the molecular and cellular pathogenesis of the disease have been elucidated. The molecular and cellular pathological research of psychiatric disorders using iPS cell technology has relatively a short history, and thus the research is expected to be further developed. In addition to studies on the molecular and cellular pathogenesis of the disease, iPS cell technology is also useful for the establishment of a system for drug screening, evaluation of drug efficacy in the preclinical stages, and evaluation of the neurotoxicity of drugs. In the future, research using iPSC technology will not only clarify the molecular and cellular pathogenesis of the disease, but will also lead to the success of drug discovery.

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The pathophysiology of psychiatric disorders is still unknown, and no fundamental treatments have been developed. Therefore, in examining the brain pathology of psychiatric disorders, it is necessary to consider possible species differences in animal models of the brain and the limitations of postmortem brain and brain imaging studies. Given the situation mentioned above, analyses at the molecular dynamics, cellular function, and neuronal circuit level using cranial neurons derived from the patients are long‐awaited. With the recent development of iPS cell technology, methods for differentiation into various cell types and organoid culture techniques that more closely resemble living organisms have been established, and iPS cells have become a powerful tool in disease research. In mental disorders research, various findings have been obtained through iPS cell‐based approaches, especially those based on rare mental disorder‐susceptibility variants. iPS cell research is making it possible to continuously monitor the entire course of mental illness from pre‐ to post‐onset, which has been difficult with previous analytical methods. “How can iPS cells be used for research on mental disorders? What are the benefits?” Here, we introduce the position of iPS cells in mental disorders research and the new paradigm that has begun to emerge with the enrollment of iPS cell research.

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