Increasing evidence indicates the elevation of proinflammatory cytokine expressions in plasma and the activation of microglia in the brains of patients with Autism Spectrum Disorder (ASD). On the other hand, neurotrophic factors such as Brain-derived neurotrophic factor (BDNF) and Neuregulin-1 (NRG1) are known as key molecules for neuronal survival and synaptic functions, leading us to consider the association of these neurotrophic factors with the pathobiology of schizophrenia and ASD. Since the expressions of BDNF and NRG1 increase in activated microglia, the levels of microglia-derived BDNF and NRG1 expressions could be higher in the brain of ASD patient which more activated microglia reside than healthy controls. Thus, elevated expressions of microglia-derived neurotrophic factors in the brain could affect the symptoms of patients with ASD.

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Epidemiological studies have shown that not only genetic factors, but also environmental factors contribute to the risks of development of neurodevelopment disorders, including autistic spectrum disorder (ASD). For example, premature birth is regarded as one of the environmental risk factors, since many survivors of extremely preterm infants (born before 28 weeks of gestation) develop ASD in later life. Among environmental risk factors, infection-induced maternal immune activation during pregnancy is thought to play the pathogenesis of neurodevelopmental disorders, such as ASD and schizophrenia. Recently, investigations in animal models of maternal immune activation revealed local changes in the brain tissue architecture in the offspring. Interestingly, similar changes in brain tissue architecture have also been reported in human ASD patients. On the other hand, it is unclear how these architectural changes contribute to the pathophysiology of ASD. We used newly established mouse models to analyze how brain architectural changes are involved in the pathogenesis of ASD. Our findings suggest that local changes in the brain tissue architecture affect distant brain regions, giving rise to abnormal animal behaviors. However, the mechanisms underlying how local changes in the brain tissue architecture affect the overall brain activities and lead to behavioral abnormalities still remain unclear.

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We here review whether behavioral phenotypes and behavioral indices of mouse experiments can be extrapolated to human psychiatry or not. So far, social interaction tests and ultrasound utterances have been used as behavioral tests equivalent to disabilities in social communication and social interactions. Regarding the restricted and repetitive behaviors, the frequency of stereotypic movements and repetitive grooming behaviors, and the reversal task in T-maze and Morris water maze are commonly used. However, it is also pointed out that these are not necessarily ensured reproducibility and replicability. We also introduce new behavioral tests recently developed and discuss about the meaning of mouse model and mouse behavioral indices.

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Autism spectrum disorders, a highly prevalent neurodevelopmental disorder, currently have no established treatment for its core symptoms. The disorders are characterized by two core symptoms including deficits in social communication and interaction, and repetitive and restricted behavior. This review article integrates previous findings testing oxytocin as a potential therapeutic for deficits in social communication and interaction in individuals with autism spectrum disorders. The author’s research group has conducted several independent clinical trials. Our previous studies have shown oxytocin-induced improvements of autistic behaviors and core symptom and their neural bases such as basically disrupted brain functions. Furthermore, we showed associations between individual differences in response to oxytocin and genotypes in oxytocin-related genes. It is reasonably expected that these findings promote a future clinical application of novel therapeutics for ASD core symptoms. However, it should also be noted that several issues to be resolved before the clinical application were remained. The issues include verification of clinically meaningful effect, detecting optimal dose and regimen, and testing safety of long term treatment especially during childhood. To resolve the issues, the author’s research group are now conducting a new research project including clinical trials to be approved by Japanese Pharmaceuticals and Medical Devices Agency.

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Genetic studies have identified rare variants strongly associated with the risk of autistic spectrum disorder (ASD) and schizophrenia (SCZ). To investigate their biological significances, genetically engineered animal models have been developed and analyzed ; however, they do not completely recapitulate these disorders. Recently, human induced pluripotent stem cells (iPSCs) have been reported as an alternative approach to understand the pathogenesis of ASD and SCZ. Since the Rett syndrome patient-derived iPSCs took a large impact in 2010, many efforts using iPSCs have been made for investigating the genetic variants including 22q11.2 deletion. Here, we review recent progress in studies of ASD and SCZ using iPSCs derived from patients with genetic variants, and discuss their advantages and futures.

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Development of iPS cell technology has made it possible to prepare neural stem cells and neuronal cells from iPS cells, and made it feasible to examine pathogenic and pathological hypotheses of schizophrenia using patient’s samples. We focused on the neurodevelopmental abnormality hypothesis that is supported as the vulnerability basis of schizophrenia. To obtain insight into abnormalities in neurodevelopmental trajectories of schizophrenia, analyses of patient-derived human iPS cells (hiPSCs) should be informative. We established hiPSCs from two schizophrenia patients with the 22q11.2 deletion, and examined the molecular pathology of microRNA (miRNA) related to abnormality of neuronal differentiation/development. Neurosphere size, neural differentiation efficiency, neurite outgrowth, cellular migration and the neurogenic-to-gliogenic competence ratio were significantly reduced in patient-derived cells. miRNA profiling detected reduced expression levels of miRNAs belonging to miR-17/92 cluster and miR-106a/b in the patient-derived neurospheres. Those miRNAs are reported to target p38, and conformingly the levels of p38 were up-regulated in the patient-derived cells. Furthermore, we confirmed an elevated expression of gliogenic (astrocyte) marker in postmortem brains from schizophrenia patients. These results suggest that a dysregulated balance of neurogenic and gliogenic competences may underlie schizophrenia.

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Autism spectrum disorder (ASD) is one of a neurodevelopmental disorder, characterized by impairments in social interactions, reduced verbal communication abilities, stereotyped repetitive behaviors and restricted interests. Genetic studies have identified candidate genetic variants, including SHANK3, NLGN3, NLGN4 and NRXN1. However, for about 70-90% of cases, the underlying molecular etiology remains unclear. Considering that most cases of ASD are sporadic, de novo mutations may contribute to a substantial fraction of the risk of ASD. Recently, genes with highly recurrent de novo possible loss-of-function mutations, including SCN2A, ANK2, SYNGAP1, ARID1B, CHD8, CHD2, SUV420H1, TBR1, ADNP, TRIP12, DYRK1, PTEN, DSCAM and POGZ have been identified in multiple unrelated patients. Among these high-confidence ASD risk genes, POGZ is one of the most recurrently mutated genes in ASD patients ; we and other groups have recently identified at least 20 independent de novo possible loss-of-function mutations in POGZ. However, the biological significance of these mutations as well as the precise role of POGZ in the brain remains unknown. To examine the significance of the Q1042R mutation in the risk for developing ASD, we established iPS cells from the patient who has the Q1042R mutation. We preliminarily found that POGZ is involved in the neuronal differentiation, providing important insights into the cellular basis of ASD.

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Schizophrenia is one of the major psychiatric disorders with the onset between late adolescence and early adulthood. Despite its high lifetime prevalence, about 1%, its pathobiology is still unclear. While many kinds of comprehensive researches had revealed a number of aspects of this disorder, there still existed some difficulties because of the methodological limitations such as inaccessibility of the live brain. However, the technology of induced pluripotent stem cells (iPSCs) allows us to investigate living brain cells from patients with neuropsychiatric disorders. There already reported some researches of iPSC-derived neurons from schizophrenia patients, and our group’s research also just getting underway. Since the technology of iPSC induction and neuronal induction from iPSCs are drastically improving, research using iPSCs will contribute to clarifying the pathobiology of neuropsychiatric disorders.

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