Mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase and plays a central role in regulation of cell growth and proliferation in response to nutrients and environmental stimuli. mTOR is found in two functionally distinct complexes, mTORC1 and mTORC2. mTORC1 is hyperactivated in many human diseases such as cancer and diabetes. In central nervous system, hyperactivation of mTORC1 is implicated in tuberous sclerosis, autism and neurodegenerative disease. In this study, we generated transgenic mice carrying mTOR kinase with gain - of - function mutations that direct selective activation of mTORC1 pathway in a spatially and temporally controlled manner. Active mTOR expression in embryonic cortex induced progressive apoptotic cell death of cortical neuronal progenitors, thereby resulting in cortical atrophy. In contrast, mTORC1 activation in postmitotic neuron led cortical hypertrophy and severe epileptic seizures. In addition, cytoplasmic inclusions were rapidly accumulated in the cortical neurons after chronic activation of mTORC1, indicative of neurodegeneration. These data demonstrate that neuronal functions of mTORC1 are different between embryonic and adult brains, and involved in human neurological diseases such as microcephaly, tuberous sclerosis and neurodegeneration.

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Autism spectrum disorder (ASD) is a childhood psychiatric disorder manifestating abnormal social behavior. Genetic contribution has been considered to be the highest in ASD among psychiatric diseases. Copy number variation (CNV) in genome is paid attention to as a cause of diseases such as cancer and psychiatric diseases including ASD and schizophrenia. The mouse model of human chromosome 15q11 - q13 duplication, one of the most frequent CNVs in ASD, was developed as a model based on clinical cases. It is an important approach to analyze phenotypes of different kinds of models in the same platform and to find their convergence. Further development of new models will be expected using recently developed genome editing techniques such as CRISPR/Cas (Clustered Regularly Interspaced Short Palindromic Repeat/ CRISPR - associated protein) .

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An approach of behavioral pharmacologic methods using animal models greatly contributed to the progress of understanding of symptoms of schizophrenia, evaluation of animal models of schizophrenia and development of therapeutic agents. Although genetically modified mice provide indispensable information for understanding the functions of target genes, studies on behavioral alteration of genetically modified mice showed inconsistent results. In this study, we used congenic dopamine D1 and D2 receptor knockout (D1R KO, D2R KO) mice and compared them simultaneously under the same conditions. We monitored their motor activity in their home cages continuously for five days as normal spontaneous activity, in which the effects of external factors are negligible. For better understanding of characteristics of motor activity, we measured the intensity of activity and the duration and number of active and inactive bouts by examining the data of the motor activity in the home cage. In addition we measured the volume of food and water intake while monitoring the motor activity. In monitoring spontaneous motor activities, D1R and D2R KO mice showed higher and lower 24 h activities, respectively, than wild type mice. We consider this novel analytical methods can be applied to analysis of behavioral alteration of animal models of schizophrenia.

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It is well known that α1,6 - fucosyltransferase (Fut8) and its products, α1,6 - fucosylated N- glycans, are highly expressed in brain tissue. Fut8 - knockout (Fut8- / - ) mice exhibited multiple behavioral abnormalities (e. g., Fut8- / - mice displayed increased locomotion and impaired working memory performance. Fut8 +/- mice showed impaired prepulse inhibition after exposure to a restraint stress) with a schizophrenia - like phenotype, suggesting that α1,6 - fucosylation plays important roles in the brain and nervous system. The balance between dopaminergic and serotonergic signaling might be disrupted in Fut8- / - mice, since the levels of serotonin metabolites were significantly decreased in both the striatum and nucleus accumbens of the mice, compared to the wild- type mice. Consistently, the treatment with an antipsychotic drug haloperidol significantly reduced hopping behaviors. Knockdown of Fut8 gene promoted improperly neurite formation via an activin- mediated signal pathway in PC12 cells. Furthermore, high frequency stimulation- induced long- term potentiation (LTP) was dramatically decreased in Fut8- /- mice. A molecular mechanism could be postulated whereby the lack of α1,6 - fucosylation in AMPARs results in aberrant heteromerization, which persistently activates cellular signaling such as through CamKII, to attenuate neuronal synaptic plasticity required for learning and memory. Thus, the present study may provide new insights as glycosylation regulates neuronal network into the underlying mechanisms responsible for schizophrenia and related disorders.

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The acoustic startle response (ASR) and its modulations are useful neurophysiological measurements in translational research. In particular, prepulse inhibition (PPI) of ASR is considered a candidate endophenotype of psychiatric diseases. However, findings from previous studies of PPI in autism spectrum disorders (ASD) have been inconsistent. Recently, we reported larger ASR magnitude to weak stimuli and prolonged peak startle latency in children with ASD. An atypical profile of ASR in ASD might therefore explain the inconsistent results in previous PPI studies. In addition, the relationship of ASR modulations to clinical characteristics of ASD is not known well. Thus, we investigated PPI with several prepulse intensities and its relationship to autistic traits and other emotional - behavioral problems in children with ASD and with typical development. Although, no significant difference for PPI or habituation was observed in ASD children compared to controls, habituation and PPI at relatively weak prepulse were negatively related to several autistic traits subscales and other emotional - behavioral problems, when considering all children. The comprehensive investigation of ASR and its modulation, including the magnitude of startle responses to weak stimuli peak startle latency, habituation, and PPI, might increase understanding of the neurophysiological impairments underlying ASD and other mental health problems in children.

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Patients of Autism Spectrum Disorder show disorder of social behavior and communication ability, and strong perseverance. This mini- review describe many types of diagnostic methods, their results of autistic patients. In addition, I show that symptom of autism are change year by year, and early diagnosis results in good prognosis.

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Fetal brain development is programmed by the maternal intrauterine environment, and disturbance of the in utero environment leads to persisting deficits in brain functions of the offspring. Testosterone is an intrauterine environmental factor, and plays significant roles in fetal development. From human and animal model studies, it has been suggested that increased intrauterine testosterone concentration triggers subsequent autistic- like behavior of the offspring. However, the synaptic mechanisms of abnormal behavior exhibited in autism spectrum syndrome remain unknown. In this review, we discuss the effects of prenatal testosterone exposure on neuronal circuitry development of the offspring. Recent genetic animal model studies of several neurodevelopmental disorders associated with autistic syndrome have demonstrated common synaptic instability, using in vivo two - photon imaging. Interestingly, the synaptic instability is also shared pathological phenotyp - e of other animal models of neurodegenerative disorders. We discuss the common synaptic instability and its importance for the pathology of diverse neuropsychiatric diseases.

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