Synapse organizers are a subset of cell adhesion molecules to induce pre-and postsynaptic differentiation and whose mutations are associated with neurodevelopmental disorders such as autism spectrum disorder, intellectual disability and schizophrenia. Accumulating evidence suggests that pre-and postsynaptic organizers form complexes in various combinations to regulate several different types of synapses depending on the respective synapse organizer complex in the brain. Thus, disease-associated mutations in the synapse organizer genes may have different effects on each respective synapse organizer complex. Recent structural analyses of the synapse organizer complexes enable to design point mutations that selectively interfere the formation of the respective synapse organizer complex. The mice carrying these designed synapse organizer mutations will be useful research tools to clarify the pathogenic mechanisms of neurodevelopmental disorders.

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Autism spectrum disorder (ASD) has a strong genetic basis. About 1000 genes have been estimated to be involved in ASD, and many of these genes determine the function of synapses. In this study, we identified a novel mutation in NLGN1 gene from ASD siblings by whole-exome sequencing. To uncover its functional significance, we conducted comprehensive analysis both in vitro and in vivo. At the in vitro level, the mutant NLGN1 showed decreased expression and abnormal sub-localization in COS7 cells overexpressing NLGN1, and the induction of dendritic spines was decreased in the primary hippocampal neurons overexpressing NLGN1. The similar phenotypes were confirmed in other NLGN1 mutations identified in ASD patients and it reinforces the significant association between NLGN1 haploinsufficiency and ASD. To address how this mutation affects in vivo phenotypes, we generated knock-in mice with a Nlgn1 mutation by CRISPR/Cas9. Similar to in vitro results, Nlgn1 mutation knock-in mice exhibited a decreased level of NLGN1 in the forebrain. In a series of behavior tests, we found several autistic traits, such as abnormal social behavior and impaired spatial memory. These results suggest that this novel NLGN1 mutation involved in ASD traits and emphasize the significant association between rare mutations in NLGN1 and neuropsychiatric disorders.

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As risk factors for schizophrenia and autism spectrum disorder, rare variants with relatively large effect sizes have been highlighted. The growing number of whole-exome sequencing and whole-genome sequencing studies have suggested their common potential pathology including abnormal chromatin remodeling, post-zygotic mutations, dysfunction of immune system and glial cells and dysregulation of microRNA. Although at this point it is unavoidable to choose functionally significant mutations out of numerous variants detected, simultaneously there is a risk to omit potentially important disease-associated mutations. In order to fully utilize those data, it is essential to develop methods to evaluate synergetic effects from mutations detected within an individual. Moreover, accumulating data validated by in vitro and in vivo experiments and applying them into analysis are required.

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Cognitive impairment in patients with psychiatric and neurodegenerative disorders, such as schizophrenia, autism, and dementia, is a serious problem, because of limited effective remedies. In order to understand pathopsysiology of cognitive impairment and develop effective treatment in neuropsychiatric disorders, the appropriate animal model and evaluation assay system are required. Touchscreen-based behavioral analysis has emerged as an automated, translatable, and reproducible approach to assessing cognition in animal models of disease and pharmacological screening. Several reports showed that human disease-related mutant mice exhibited cognitive impairments in touchscreen-based visual discrimination (VD) task. We analyzed cognitive function of animal model for psychiatric disorders using a touchscreen-based VD task. In this review, we introduce touchscreen-based VD and reversal learning tests to analyze cognitive function in animal models for neuropsychiatric disorders.

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The brain consists of various brain regions, and each brain region has specific functions such as motor regulation, sensory perception and cognitive function. Although a number of cellular mechanisms underlying brain functions have been revealed by focusing on specific local brain areas, systems analysis of the whole brain is a prerequisite to further understand the functional and anatomical relationships of the brain and their alterations in neuropsychiatric disorders. To illustrate whole-brain structural and functional maps at cellular and subcellular resolutions, whole-brain imaging techniques using fluorescent microscopy have been recently developed together with quantitative analysis methods for the whole-brain data. These state-of-the-art imaging analyses are currently used for brain-wide neuronal projection mapping, cell-type specific mapping and neuronal activation mapping, and such analyses are applicable to pathological studies using animal models of neuropsychiatric disorders. Unbiased and hypothesis-free comparison across the whole brain is expected to identify network mechanisms that regulate various neurobiological functions and dysfunctions.

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Social and environmental stress induces emotional changes, such as depression and elevated anxiety, and precipitates mental illnesses including depression. Although psychological stress activates the dopaminergic system projecting to the medial prefrontal cortex (mPFC) , its role remains poorly understood. Recent studies using mouse stress models have shown that short-term stress augments stress resilience through dopaminergic response and activation of dopamine D1 receptor in mPFC, whereas prolonged stress attenuates the mPFC dopaminergic response and induces emotional changes. Concomitant with these changes, short-term stress induces dendritic hypertrophy, and prolonged stress induces dendritic atrophy, in mPFC excitatory neurons. The mechanisms underlying the dendritic hypertrophy and atrophy induced by stress appear to be different, as D1 receptor in mPFC is critical only for the short-term stress-induced dendritic hypertrophy. These findings suggest that stress regulates stress resilience through morphological alterations of mPFC excitatory neurons, and highlight the molecular mechanisms underlying these morphological alterations as novel targets for drug discovery in mental and other stress-related illnesses.

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Autism spectrum disorders and schizophrenia are thought to be neurodevelopmental diseases. Both of those have a prevalence of about 1%, which impair sociality and communication. Interestingly, both disorders commonly exhibit the impaired auditory capabilities such as hypersensitivity / insensitivity to sound and delay of language development for autism spectrum disorders and auditory hallucination and language illusion for schizophrenia. Human chromosomes 22q11 and 16p11 abnormalities frequently cause these mental diseases, but at the same time, some of these patients as well as their model animals have ear problem and sensory hearing loss. Does these hearing deficits or auditory cognitive dysfunction represent the cause or the actual condition of these diseases? From the current viewpoint of the top-down information processing from the frontal lobe cortex, I would like to consider biological implication of the auditory physiology and otolaryngological pathology of autistic spectrum disorder and schizophrenia.

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The basal ganglia are important neural substrates that control not only motor functions but also advanced brain functions and dysfunctions including decision making and drug addiction. In the basal ganglia circuit, there are two important pathways; the direct and indirect striatal pathways, which are controlled by dopamine. Various techniques that activate or inactive selectively the direct or indirect pathway neurons have revealed the function of each pathway. Here we review the basal ganglia circuit mechanisms in decision making and drug addiction, especially the dopaminergic modulation of the direct and indirect pathways. These circuit mechanisms will give us insights into the pathophysiology of mental disorders including drug addiction.

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