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Photon upconversion (UC) from near-infrared (NIR) light to visible light has enabled optogenetic manipulations in deep tissues. However, materials for NIR optogenetics have been limited to inorganic UC nanoparticles. Herein, NIR-light-triggered optogenetics using biocompatible, organic TTA-UC hydrogels is reported. To achieve triplet sensitization even in highly viscous hydrogel matrices, a NIR-absorbing complex is covalently linked with energy-pooling acceptor chromophores, which significantly elongates the donor triplet lifetime. The donor and acceptor are solubilized in hydrogels formed from biocompatible Pluronic F127 micelles, and heat treatment endows the excited triplets in the hydrogel with remarkable oxygen tolerance. Combined with photoactivatable Cre recombinase technology, NIR-light stimulation successfully performs genome engineering resulting in the formation of dendritic-spine-like structures of hippocampal neurons.

The adult human brain consists of approximately a hundred billion neurons, which are connected via synapses. The pattern and strength of the synaptic connections are constantly changing (synaptic plasticity), and these changes are considered to underlie learning, memory, and personality. Many psychiatric disorders have been related to disturbances in synaptogenesis and subsequent plasticity. In this review, we summarize findings of synaptic disturbance and its involvement in the pathogenesis and/or pathophysiology of psychiatric disorders. We will focus on schizophrenia, because this condition has a high proven heritability, which offers more unambiguous insights into the biological origins of not only schizophrenia but also related psychiatric disorders. To demonstrate the involvement of synaptopathy in psychiatric disorders, we discuss what knowledge is missing at the circuits level, and what new technologies are needed to achieve a comprehensive understanding of synaptopathy in psychiatric disorders.

Although synaptic abnormalities are implicated in the pathophysiology of schizophrenia, it remains unclear whether the synaptic pathology is a casual mechanism that controls the behaviors, or whether it is merely a secondary consequence of the disorder. Chaotic behavior and fluctuations in the pathophysiology of schizophrenia also make it challenging to gain a better understanding of the disorder. In this study, we focused on the disorders in a constructive and multi-scale manner, we attempt to elucidate the causal relationships across the hierarchy between schizophrenia-related genes and disease-related behaviors.

Behavioral learning is driven by adaptive changes in the activation of behaviorally relevant neuronal ensembles. This learning-specific reorganization of neuronal circuits is correlated with activity-dependent modifications of synaptic dynamics. However, a definitive causal link remains to be established. How is synaptic plasticity distributed among circuits to eventually shape behavioral learning? A multi-scale understanding of the progressive plasticity is hindered by the lack of techniques for monitoring and manipulating these events. The current rise of synaptic optogenetics, especially combined with brain-wide circuit imaging, opens an entirely new avenue for studying causality at multiple scales. In this review, we summarize these technical achievements and discuss challenges in linking the plasticity across levels to elucidate the multi-scale mechanisms of learning.

Mutations in the gene encoding the chromatin remodeler CHD8 are strongly associated with autism spectrum disorder (ASD). CHD8 haploinsufficiency also results in autistic phenotypes in humans and mice. Although myelination defects have been observed in individuals with ASD, whether oligodendrocyte dysfunction is responsible for autistic phenotypes has remained unknown. Here we show that reduced expression of CHD8 in oligodendrocytes gives rise to abnormal behavioral phenotypes in mice. CHD8 was found to regulate the expression of many myelination-related genes and to be required for oligodendrocyte maturation and myelination. Ablation of Chd8 specifically in oligodendrocytes of mice impaired myelination, slowed action potential propagation and resulted in behavioral deficits including increased social interaction and anxiety-like behavior, with similar effects being apparent in Chd8 heterozygous mutant mice. Our results thus indicate that CHD8 is essential for myelination and that dysfunction of oligodendrocytes as a result of CHD8 haploinsufficiency gives rise to several neuropsychiatric phenotypes.

Betaine is known to act against various biological stresses and its levels were reported to be decreased in schizophrenia patients. Using Chdh (a gene for betaine synthesis)-deficient mice and betaine-supplemented inbred mice, we assessed the role of betaine in psychiatric pathophysiology, and its potential as a novel psychotherapeutic, by leveraging metabolomics, behavioral-, transcriptomics and DNA methylation analyses. The Chdh-deficient mice revealed remnants of psychiatric behaviors along with schizophrenia-related molecular perturbations. Betaine supplementation elicited genetic background-dependent improvement in cognitive performance, and suppressed methamphetamine (MAP)-induced behavioral sensitization. Furthermore, betaine rectified the altered antioxidative and proinflammatory responses induced by MAP and in vitro phencyclidine treatments. Notably, betaine levels were decreased in the postmortem brains from schizophrenia, and a coexisting elevated carbonyl stress, a form of oxidative stress, demarcated a subset of schizophrenia with “betaine deficit-oxidative stress pathology”. We revealed the decrease of betaine levels in glyoxylase 1 (GLO1)-defícient hiPSCs, which shows elevated carbonyl stress, and the efficacy of betaine in alleviating it, thus supporting a causal link between betaine and oxidative stress conditions. Furthermore, a CHDH variant, rs35518479, was identified as a cis-expression quantitative trait locus (QTL) for CHDH expression in postmortem brains from schizophrenia, allowing genotype-based stratification of schizophrenia patients for betaine efficacy. In conclusion, the present study underscores the potential benefit of betaine in a subset of schizophrenia.

Recently, optogenetic techniques have emerged as a method to optically manipulate molecular and cellular events in target cells both in vitro and in vivo. Optogenetics results from the fruitful combination of optics and genetic engineering, maximizing the advantages of each discipline. These advantages are optical control through the manipulation of wavelength and light intensity on the millisecond timescale, and specific gene expression and gene product trafficking with subcellular precision. This kind of fine-tuning cannot be achieved using traditional methods. Therefore, optogenetic techniques have brought a revolution to neuroscience. In this review, we provide a concise summary of the history and recent advances of optogenetics, focusing in particular on applications for psychiatric research.

Schizophrenia is a chronic, severe, and disabling brain disorder, with an estimated lifetime prevalence of 0.7%. Despite its relatively low prevalence, the onset of schizophrenia usually occurs early in life, resulting in a severe lifelong disability for patients and increasing the economic and care burden on their families. This makes schizophrenia one of the most catastrophic mental illnesses. Although the etiology of schizophrenia remains poorly understood, clinical, genetic, and pharmacological studies have indicated that its pathophysiology involves synaptic disturbances. Here, I review the evidence suggesting synaptic disturbance as the causal pathophysiology of schizophrenia and discuss the possible application of synaptic intervention as a novel therapeutic strategy for schizophrenia.

A fast, high-sensitivity photothermal microscope was developed by implementing a spatially segmented balanced detection scheme into a laser scanning microscope. We confirmed a 4.9 times improvement in signal-to-noise ratio in the spatially segmented balanced detection compared with that of conventional detection. The system demonstrated simultaneous bi-modal photothermal and confocal fluorescence imaging of transgenic mouse brain tissue with a pixel dwell time of 20 μs. The fluorescence image visualized neurons expressing yellow fluorescence proteins, while the photothermal signal detected endogenous chromophores in the mouse brain, allowing 3D visualization of the distribution of various features such as blood cells and fine structures probably due to lipids. This imaging modality was constructed using compact and cost-effective laser diodes, and will thus be widely useful in the life and medical sciences.

Dentritic spines are small membrane protrusions. Their regulation is thought to be important for memory storage, but the links between dentric spines and memory have been largely correlational because of a luck of techniques for manipulating individual spines. To overcome this problem, we have developed a novel synaptic optoprobe, AS-PaRac1, which is unique not only because it specifically labels recently potentiated spines, but also because it becomes possible to selectively shrink spines containing AS-PaRac1. This indicates that AS-PaRac1 can be use to specifically visualize the recently "written spines" and that the erasure of these spines is possible upon excitation with blue light. Using in vivo two-photon imaging, synaptic potentiation was visualized during active remodeling of the neocortex. Upon learning a motor skill, AS-PaRac1 expression was induced in a relatively small number of neurons, in which approximately 8% of spines were tagged by AS-PaRac1. The labeled spines were broadly distributed throughout the dendritic tree. Excitation with blue light induced shrinkage of learning related spines and disrupted the acquired motor learning. In contrast, the erasure of a similar number of learning-irrelevant spines did not affect task performance. This novel light-dependent tool will open up new areas of memory research, and will additionally shed light on the neural networks that determine who we are.

Calcineurin is required for long-term depression and activity-dependent spine shrinkage, and calcineurin mutations have been identified in patients with schizophrenia. Moreover, mice with conditional knockout of calcineurin B (CNB-KO) exhibit behavioral abnormalities suggestive of schizophrenia. Changes in the dendritic spines of these mice, however, have not been investigated. We therefore examined the dendritic spines of CNB-KO mice, and observed a significant reduction in small spines and an increase in large spines in the prefrontal and visual cortices. The effect of CNB-KO on the spine sizes was relatively moderate, possibly due to the presence of spontaneous fluctuations (dynamics) in the dendritic spines themselves. Thus, CNB-KO mice showed a spine phenotype similar to those recently reported in patients with schizophrenia.

Summary Dendritic spines are the major loci of synaptic plasticity and are considered as possible structural correlates of memory. Nonetheless, systematic manipulation of specific subsets of spines in the cortex has been unattainable, and thus, the link between spines and memory has been correlational. We developed a novel synaptic optoprobe, AS-PaRac1 (activated synapse targeting photoactivatable Rac1), which can label recently potentiated spines specifically, and induce the selective shrinkage of AS-PaRac1-containing spines. In vivo imaging of AS-PaRac1 revealed that a motor learning induced substantial synaptic remodelling in a small subset of neurons. The acquired motor learning was disrupted by the optical shrinkage of the potentiated spines, whereas it was not affected by the identical manipulation of spines evoked by a distinct motor task in the same cortical region. Taken together, our results demonstrate that a newly acquired motor skill depends on the formation of a task-specific dense synaptic ensemble.

Background Genetic studies have implicated disrupted-in-schizophrenia-1 (DISC1) as a risk factor for a wide range of mental conditions, including schizophrenia. Because N-methyl-D-aspartate receptor (NMDAR) dysfunction has been strongly linked to the pathophysiology of these conditions, we examined whether the NMDAR is a potential target of DISC1. Methods DISC1 was knocked down with a small inference RNA. NMDAR-mediated currents were recorded and NMDAR expression was measured. Results We found that cellular knockdown of DISC1 significantly increased NMDAR currents in cortical cultures, which were accompanied by an increase in the expression of NMDAR subunit, GluN2A. NMDAR-mediated synaptic response in prefrontal cortical pyramidal neurons was also increased by DISC1 knockdown in vivo. The effect of DISC1 knockdown on NMDAR currents in cortical cultures was blocked by protein kinase A (PKA) inhibitor, occluded by PKA activator, and prevented by phosphodiesterase 4 inhibitor. Knockdown of DISC1 caused a significant increase of cyclic adenosine monophosphate response element-binding protein (CREB) activity. Inhibiting CREB prevented the DISC1 deficiency-induced increase of NMDAR currents and GluN2A clusters. Conclusions Our results suggest that DISC1 exerts an important impact on NMDAR expression and function through a phosphodiesterase 4/PKA/CREB-dependent mechanism, which provides a potential molecular basis for the role of DISC1 in influencing NMDAR-dependent cognitive and emotional processes.

Activity-dependent competition of synapses plays a key role in neural organization and is often promoted by GABA; however, its cellular bases are poorly understood. Excitatory synapses of cortical pyramidal neurons are formed on small protrusions known as dendritic spines, which exhibit structural plasticity. We used two-color uncaging of glutamate and GABA in rat hippocampal CA1 pyramidal neurons and found that spine shrinkage and elimination were markedly promoted by the activation of GABAA receptors shortly before action potentials. GABAergic inhibition suppressed bulk increases in cytosolic Ca(2+) concentrations, whereas it preserved the Ca(2+) nanodomains generated by NMDA-type receptors, both of which were necessary for spine shrinkage. Unlike spine enlargement, spine shrinkage spread to neighboring spines (

Memories are crucial to the cognitive essence of who we are as human beings. Accumulating evidence has suggested that memories are stored as a subset of neurons that probably fire together in the same ensemble. Such formation of cell ensembles must meet contradictory requirements of being plastic and responsive during learning, but also stable in order to maintain the memory. Although synaptic potentiation is presumed to be the cellular substrate for this process, the link between the two remains correlational. With the application of the latest optogenetic tools, it has been possible to collect direct evidence of the contributions of synaptic potentiation in the formation and consolidation of cell ensemble in a learning task specific manner. In this review, we summarize the current view of the causative role of synaptic plasticity as the cellular mechanism underlying the encoding of memory and recalling of learned memories. In particular, we will be focusing on the latest optoprobe developed for the visualization of such “synaptic ensembles.” We further discuss how a new synaptic ensemble could contribute to the formation of cell ensembles during learning and memory. With the development and application of novel research tools in the future, studies on synaptic ensembles will pioneer new discoveries, eventually leading to a comprehensive understanding of how the brain works.

Recently, optogenetic techniques have emerged as a method to optically manipulate molecular and cellular events in target cells both in vitro and in vivo. Optogenetics results from the fruitful combination of optics and genetic engineering, maximizing the advantages of each discipline. These advantages are optical control through the manipulation of wavelength and light intensity on the millisecond timescale, and specific gene expression and gene product trafficking with subcellular precision. This kind of fine-tuning cannot be achieved using traditional methods. Therefore, optogenetic techniques have brought a revolution to neuroscience. In this review, we provide a concise summary of the history and recent advances of optogenetics, focusing in particular on applications for psychiatric research.

Dendritic spine generation and elimination play an important role in learning and memory, the dynamics of which have been examined within the neocortex in vivo. Spine turnover has also been detected in the absence of specific learning tasks, and is frequently exaggerated in animal models of autistic spectrum disorder (ASD). The present study aimed to examine whether the baseline rate of spine turnover was activity-dependent. This was achieved using a microfluidic brain interface and open-dura surgery, with the goal of abolishing neuronal Ca2+ signaling in the visual cortex of wild-type mice and rodent models of fragile X syndrome (Fmr1 knockout [KO]). In wild-type and Fmr1 KO mice, the majority of baseline turnover was found to be activity-independent. Accordingly, the application of matrix metalloproteinase-9 inhibitors selectively restored the abnormal spine dynamics observed in Fmr1 KO mice, without affecting the intrinsic dynamics of spine turnover in wild-type mice. Such findings indicate that the baseline turnover of dendritic spines is mediated by activity-independent intrinsic dynamics. Furthermore, these results suggest that the targeting of abnormal intrinsic dynamics might pose a novel therapy for ASD.

Although there is an urgent need for biological diagnosis of bipolar disorder (BD), there have been no established biomarkers. Gene expression analysis in lymphoblastoid cells (LCLs) would be a promising candidate for biomarkers. In this study, 17 candidate genes were measured in the LCLs of patients with BD. Using the data of the first set of samples (13 patients with bipolar I disorder and 21 controls), three genes, ANK3, RASGRP1 and POLG1, were selected by the logistic regression analysis with a stepwise method. Using the discriminant function generated by this analysis, the first sample was discriminated with the sensitivity of 76% and specificity of 85%. By applying the same function to the second sample set (18 patients with bipolar I and 37 controls), bipolar I disorder could be discriminated from the controls with the sensitivity of 44% and specificity of 81% (χ(2)=3.97, P=0.046). This study was the first to suggest a possible role of gene expression analysis of ANK3, RASGRP1 and POLG1 in the LCLs as potential biomarkers of BD.

Glutamate, the principal excitatory neurotransmitter of the brain, participates in a multitude of physiologic and pathologic processes, including learning and memory. Glutathione, a tripeptide composed of the amino acids glutamate, cysteine, and glycine, serves important cofactor roles in antioxidant defense and drug detoxification, but glutathione deficits occur in multiple neuropsychiatric disorders. Glutathione synthesis and metabolism are governed by a cycle of enzymes, the γ-glutamyl cycle, which can achieve intracellular glutathione concentrations of 1-10 millimolar. Because of the considerable quantity of brain glutathione and its rapid turnover, we hypothesized that glutathione may serve as a reservoir of neural glutamate. We quantified glutamate in HT22 hippocampal neurons, PC12 cells and primary cortical neurons after treatment with molecular inhibitors targeting three different enzymes of the glutathione metabolic cycle. Inhibiting 5-oxoprolinase and γ-glutamyl transferase, enzymes that liberate glutamate from glutathione, leads to decreases in glutamate. In contrast, inhibition of γ-glutamyl cysteine ligase, which uses glutamate to synthesize glutathione, results in substantial glutamate accumulation. Increased glutamate levels following inhibition of glutathione synthesis temporally precede later effects upon oxidative stress.

Regulatory mechanisms governing the sequence from progenitor cell proliferation to neuronal migration during corticogenesis are poorly understood. Here we report that phosphorylation of DISC1, a major susceptibility factor for several mental disorders, acts as a molecular switch from maintaining proliferation of mitotic progenitor cells to activating migration of postmitotic neurons in mice. Unphosphorylated DISC1 regulates canonical Wnt signalling via an interaction with GSK3β, whereas specific phosphorylation at serine 710 (S710) triggers the recruitment of Bardet-Biedl syndrome (BBS) proteins to the centrosome. In support of this model, loss of BBS1 leads to defects in migration, but not proliferation, whereas DISC1 knockdown leads to deficits in both. A phospho-dead mutant can only rescue proliferation, whereas a phospho-mimic mutant rescues exclusively migration defects. These data highlight a dual role for DISC1 in corticogenesis and indicate that phosphorylation of this protein at S710 activates a key developmental switch.

The pathological mechanisms underlying schizophrenia are unclear. Although genetic susceptibility factors for schizophrenia likely influence neurodevelopmental processes, the onset of the disease is in adolescence and young adulthood. Here we review recent literatures implicating neurodevelopmental deficits in schizophrenia and discuss how genetic factors are involved in the processes toward onset of the disease. We emphasize the importance of postnatal glutamate synapse development in the pathology of the disorder. These genetic risk factors contribute to the process possibly in a synergistic manner. The notion of signal pathways involving more than one genetic factor is in accord with the multifactorial nature of schizophrenia.

Summary We describe a strategy for developing hydrophilic chemical cocktails for tissue delipidation, decoloring, refractive index (RI) matching, and decalcification, based on comprehensive chemical profiling. More than 1,600 chemicals were screened by a high-throughput evaluation system for each chemical process. The chemical profiling revealed important chemical factors: salt-free amine with high octanol/water partition-coefficient (logP) for delipidation, N-alkylimidazole for decoloring, aromatic amide for RI matching, and protonation of phosphate ion for decalcification. The strategic integration of optimal chemical cocktails provided a series of CUBIC (clear, unobstructed brain/body imaging cocktails and computational analysis) protocols, which efficiently clear mouse organs, mouse body including bone, and even large primate and human tissues. The updated CUBIC protocols are scalable and reproducible, and they enable three-dimensional imaging of the mammalian body and large primate and human tissues. This strategy represents a future paradigm for the rational design of hydrophilic clearing cocktails that can be used for large tissues.

Neuregulin-1 (NRG1) and Disrupted-in-Schizophrenia-1 (DISC1) are promising susceptibility factors for schizophrenia. Both are multifunctional proteins with roles in a variety of neurodevelopmental processes, including progenitor cell proliferation, migration, and differentiation. Here, we provide evidence linking these factors together in a single pathway, which is mediated by ErbB receptors and PI3K/Akt. We show that signaling by NRG1 and NRG2, but not NRG3, increase expression of an isoform of DISC1 in vitro. Receptors ErbB2 and ErbB3, but not ErbB4, are responsible for transducing this effect, and PI3K/Akt signaling is also required. In NRG1 knockout mice, this DISC1 isoform is selectively reduced during neurodevelopment. Furthermore, a similar decrease in DISC1 expression is seen in β-site amyloid precursor protein cleaving enzyme–1 (BACE1) knockout mice, in which NRG1/Akt signaling is reportedly impaired. In contrast to neuronal DISC1 that was reported and characterized, expression of DISC1 in other types of cells in the brain has not been addressed. Here we demonstrate that DISC1, like NRG and ErbB proteins, is expressed in neurons, astrocytes, oligodendrocytes, microglia, and radial progenitors. These findings may connect NRG1, ErbBs, Akt, and DISC1 in a common pathway, which may regulate neurodevelopment and contribute to susceptibility to schizophrenia.

Synaptic spines are dynamic structures that regulate neuronal responsiveness and plasticity. Here we describe a role for the schizophrenia risk factor, Disrupted-in-Schizophrenia 1 (DISC1), in the maintenance of spine morphology and function. We show that DISC1 anchors Kalirin-7 (Kal-7) thereby regulating access of Kal-7 to Rac1 and so controlling the duration and intensity of Rac1 activation in response to NMDA receptor activation in cortical culture as well as in vivo brain. This offers explanation for why Rac1 and its activator (Kal-7) serve as key mediators of spine enlargement and that constitutive Rac1 activation decreases spine size. This novel mechanism likely underlies disturbances in glutamatergic neurotransmission frequently reported in schizophrenia that can lead to alteration of dendritic spines with consequential major pathological changes in brain function. Furthermore, the concept of a “signalosome” involving disease-associated factors, such as DISC1 and glutamate, may well contribute to the multifactorial and polygenetic characteristics of schizophrenia.

Schizophrenia (SZ) is primarily an adult psychiatric disorder in which disturbances caused by susceptibility genes and environmental insults during early neurodevelopment initiate neurophysiological changes over a long time course, culminating in the onset of full-blown disease nearly two decades later. Aberrant postnatal brain maturation is an essential mechanism underlying the disease. Currently, symptoms of SZ are treated with anti-psychotic medications that have variable efficacy and severe side effects. There has been much interest in the prodromal phase and the possibility of preventing SZ by interfering with the aberrant postnatal brain maturation associated with this disorder. Thus, it is crucial to understand the mechanisms that underlie the long-term progression to full disease manifestation to identify the best targets and approaches towards this goal. We believe that studies of certain SZ genetic susceptibility factors with neurodevelopmental implications will be key tools in this task. Accumulating evidence suggests that neuregulin-1 (NRG1) and disrupted-in-schizophrenia-1 (DISC1) are probably functionally convergent and play key roles in brain development. We provide an update on the role of these emerging concepts in understanding the complex time course of SZ from early neurodevelopmental disturbances to later onset and suggest ways of testing these in the future.

Animal behavior follows rewards Animal behavior is learned and reinforced by rewards. On a molecular level, the reward comes in the form of the neurotransmitter, dopamine, which modulates synapses. The exact timing and mechanism of this process remain unknown. Using optical stimulation, Yagishita et al. found that dopaminergic modulation involved dendritic spine enlargement only during an extremely narrow time window. Known as reinforcement plasticity, this cellular basis for learning could provide insight into psychiatric disorders involving dopaminergic regulation, such as depression, drug addiction, and schizophrenia. Science , this issue p. 1616

We demonstrate the use of intensity-modulated laser diodes to implement pump-probe microscopy and achieved sub-diffraction resolution imaging with shot-noise limited sensitivity with a scheme of balanced detection. This technique has several applications for various types of induced transmission change, including excited-state absorption, ground state absorption bleaching and stimulated emission. By using our technique, biological imaging of mouse T cells and the axons of neurons in the cerebral cortex was demonstrated.

Drug discovery in psychiatry has been limited to chemical modifications of compounds originally discovered serendipitously. Therefore, more mechanism-oriented strategies of drug discovery for mental disorders are awaited. Schizophrenia is a devastating mental disorder with synaptic disconnectivity involved in its pathophysiology. Reduction in the dendritic spine density is a major alteration that has been reproducibly reported in the cerebral cortex of patients with schizophrenia. Disrupted-in-Schizophrenia-1 (DISC1), a factor that influences endophenotypes underlying schizophrenia and several other neuropsychiatric disorders, has a regulatory role in the postsynaptic density in association with the NMDA-type glutamate receptor, Kalirin-7, and Rac1. Prolonged knockdown of DISC1 leads to synaptic deterioration, reminiscent of the synaptic pathology of schizophrenia. Thus, we tested the effects of novel inhibitors to p21-activated kinases (PAKs), major targets of Rac1, on synaptic deterioration elicited by knockdown expression of DISC1. These compounds not only significantly ameliorated the synaptic deterioration triggered by DISC1 knockdown but also partially reversed the size of deteriorated synapses in culture. One of these PAK inhibitors prevented progressive synaptic deterioration in adolescence as shown by in vivo two-photon imaging and ameliorated a behavioral deficit in prepulse inhibition in adulthood in a DISC1 knockdown mouse model. The efficacy of PAK inhibitors may have implications in drug discovery for schizophrenia and related neuropsychiatric disorders in general.

Peripheral samples, such as blood and skin, have been used for decades in psychiatric research as surrogates for central nervous system samples. Although the validity of the data obtained from peripheral samples has been questioned and other state-of-the-art techniques, such as human brain imaging, genomics, and induced pluripotent stem cells, seem to reduce the value of peripheral cells, accumulating evidence has suggested that revisiting peripheral samples is worthwhile. Here, we re-evaluate the utility of peripheral samples and argue that establishing an understanding of the common signaling and biological processes in the brain and peripheral samples is required for the validity of such models. First, we present an overview of the available types of peripheral cells and describe their advantages and disadvantages. We then briefly summarize the main achievements of omics studies, including epigenome, transcriptome, proteome, and metabolome analyses, as well as the main findings of functional cellular assays, the results of which imply that alterations in neurotransmission, metabolism, the cell cycle, and the immune system may be partially responsible for the pathophysiology of major psychiatric disorders such as schizophrenia. Finally, we discuss the future utility of peripheral samples for the development of biomarkers and tailor-made therapies, such as multimodal assays that are used as a battery of disease and trait pathways and that might be potent and complimentary tools for use in psychiatric research.

Disturbance in the synapse has been suggested in the pathology of schizophrenia, especially through examination of autopsied brains from patients with the disease. Nonetheless, it has been unclear whether and how such disturbance is associated with the onset and progression of the disease in young adulthood. Some studies with magnetic resonance spectroscopy (MRS) have suggested that overpruning of dendritic spines may occur in the prodromal and early stages of schizophrenia. In addition, our recent study indicates that DISC1, a promising risk factor for schizophrenia, has a crucial role in the maintenance of the dendritic spine in association with activation of the NMDA-type glutamate receptor.1 Disturbance of spine maintenance can be linked to aberrant synaptic pruning during postnatal brain maturation. Biological studies with genetic models may provide us with an opportunity to validate experimentally the synaptic pruning theory for schizophrenia. An integrative strategy of brain imaging and cell biology may be a promising approach to address a key biological question for mental illnesses.

Schizophrenia (SZ) is a highly polygenic disease with strong genetic predisposition. Although genetic susceptibility factors for SZ are likely to have an influence in some brain regions and related neural circuits during neurodevelopment, direct proof for spatiotemporal causality in the development of SZ, and the alteration of what gene function at what brain region during what developmental stage, remains to be elucidated. Gene manipulation by viral vector stereotaxically injected into a specific brain region is now becoming available for psychiatric research. This technique has several advantages, e.g., the exceptional spatiotemporal control, simultaneous manipulation of multiple genes, and its simple protocol. These properties can make this technique one of the most valuable approaches for research in SZ, which is a complex brain disorder with multifactorial, genetic, and developmental features. This review summarizes the benefits and actual use of this technique together with discussion of spatiotemporal aspect for SZ.

Schizophrenia (SZ) is a highly polygenic disease with strong genetic predisposition. Although genetic susceptibility factors for SZ are likely to have an influence in some brain regions and related neural circuits during neurodevelopment, direct proof for spatiotemporal causality in the development of SZ, and the alteration of what gene function at what brain region during what developmental stage, remains to be elucidated. Gene manipulation by viral vector stereotaxically injected into a specific brain region is now becoming available for psychiatric research. This technique has several advantages, e.g., the exceptional spatiotemporal control, simultaneous manipulation of multiple genes, and its simple protocol. These properties can make this technique one of the most valuable approaches for research in SZ, which is a complex brain disorder with multifactorial, genetic, and developmental features. This review summarizes the benefits and actual use of this technique together with discussion of spatiotemporal aspect for SZ.