Single‐cell analysis, which enables genome‐wide gene expression analysis at the single‐cell resolution, identified more cell subtypes than we previously imagined. It has also contributed to identifying cell‐type‐specific risk genes in various disorders. In particular, it has proven to be an effective tool in identifying cell‐type‐specific pathologies in conditions such as “neurodevelopmental and neuropsychiatric disorders,” that cannot be fully explained by the deficit of neuropathologies. In 2015, the National Institute of Mental Health (NIMH) launched the PsychENCODE consortium, an interdisciplinary psychiatry consortium focused on neuropsychiatric disorders using large‐scale postmortem human brain data. The first phase of this initiative was published in Science in 2018, followed by phase 2 in 2024. Since PsychENCODE Phase 2 (PsychENCODE2) is a project focused on single‐cell and multi‐omics approaches, I will introduce new findings reported in the latest PsychENCODE2.

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Many genomic and epigenomic studies have been conducted on postmortem brains to elucidate the etiology of psychiatric disorders, such as schizophrenia and bipolar disorder. However, because the brain is an extremely heterogeneous tissue composed of many cell types, it is difficult to distinguish whether findings in studies using bulk tissue simply reflect differences in the proportions of cell types within the tissue or whether they actually indicate disease‐related phenotypes. To address this issue, we isolated neuronal and non‐neuronal cell nuclei from the postmortem brains of patients with psychiatric disorders and performed omics analyses. In this article, we review recent studies on somatic mutation in patients with schizophrenia and DNA methylation analysis in patients with bipolar disorder. Both studies revealed findings specific to neurons in the patient groups, and further validation is expected.

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Synapses, which mediate communication between neurons, include a diverse array of proteins. Among these, the postsynaptic density (PSD) contains over 1,000 distinct proteins that play crucial roles in maintaining synaptic structure and function. Proteomic analyses using mass spectrometry have contributed to the identification and quantification of PSD‐localized proteins. In recent years, research has increasingly focused on elucidating how the protein composition of synapses and the PSD changes under various physiological conditions and in neuropsychiatric disorders, with the aim of advancing our understanding of brain function and disease pathophysiology. This review provides an overview of PSD‐localized proteins and discusses changes in PSD protein composition during postnatal development and in neuropsychiatric disorders, incorporating recent findings from the authors. Furthermore, I discuss how these insights could contribute to unraveling the molecular basis of neuropsychiatric disorders and developing novel therapeutic strategies.

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Synaptic plasticity is a critical mechanism underlying the long‐term retention of information in the brain. In particular, dendritic spines-postsynaptic structure of excitatory synapses located in the neocortex, hippocampus, and striatum-play a pivotal role in synaptic plasticity, named structural long‐term potentiation (sLTP) . sLTP has been extensively studied in the hippocampus and striatum. In contrast, its mechanisms in the neocortex remain poorly understood, although the neocortex is a central brain region involved in processing of sensory, motor and emotional information. Notably, synaptic plasticity declines with maturation in the neocortex according to ex vivo studies, but spine plasticity persists into adulthood based on in vivo observations, presenting an unresolved enigma. Our recent findings reveal that sLTP is prominent during juvenile but becomes suppressed in adulthood through regulation by microglia via TNF‐α. However, this inhibition can be reversed in adulthood by noradrenaline (NA) , which acts through microglial β2‐adrenergic receptors to promote sLTP. Moreover, this signaling contributes to the establishment of observational fear learning (OFL) . These results highlight an emergence of developmental balance of microglia and noradrenaline to modulate neocortical synaptic plasticity and learning in the neocortex.

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One hundred trillion synapses organize the human brain network. Synaptic functions are not limited to mediating communication between neurons. Synapses are equipped with various chemical properties, including neurotransmitters, allowing the relatively fixed neural network to be plastic and thereby inducing diversity in animal behavior. Upon exposure to a threat, animals launch a fear response in three steps : threat detection, fear perception, and behavioral expression of fear, all of which processes are modified by different types of synapses. Importantly, the fear response is not constant but rather flexible, depending on the animals’ internal and external states, suggesting that diverse organismal states could be integrated into the neural network through synaptic chemical functions. In addition to the acute fear response, long‐term aftereffects occur following robust or continuous exposure to a threat, as seen in mental disorders such as anxiety disorder, depression, and post‐traumatic stress disorder, which also involve various types of synapses. Here, I summarize the various synapses that could organize network plasticity in the fear response and long‐term aftereffects.

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Synapses are fundamental for the formation of neural circuits in the brain and are essential for regulating higher brain functions such as learning, memory and emotions. Moreover, synapses exhibit a diversity of structures and functions across different brain regions. To gain a deeper understanding of complex brain functions and elucidate the pathological mechanisms underlying psychiatric and neurological disorders, it is crucial to characterize the protein components and distinctive molecular mechanisms specific to each synapse types. However, conventional biological approaches have struggled to spatially isolate specific synapses from different brain regions and comprehensively analyze their protein components. To address this challenge, biotin ligase‐based proximity labeling (BioID) has recently been applied to spatial proteome analysis in the brain, leading to the development of the “in vivo BioID (iBioID) ” technique. iBioID enables comprehensive proteome analysis of specific synapse types and synaptic clefts in the brain with high spatial resolution. In this brief review, we summarize recent advancements in iBioID‐based synaptic proteome techniques in the brain. Additionally, we introduce a novel molecular mechanism in astrocyte‐neuronal synapses using our newly developed iBioID technique.

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