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Symposia Frontiers in animal research on neurodevelopmental diseases／自閉症研究最前線：モデル動物のさらなる可能性を求めて 2S1-1 Effect of paternal aging on behavior of offspring in animal models of neurodevelopmental diseases Noriko Osumi Tohoku University Graduate School of Medicine, Department of Developmental Neuroscience Recent studies suggested that advanced paternal age could be a risk for some psychiatric diseases like autism and schizophrenia, and thus how paternal aging affects their offspring’s health is becoming a fundamental issue. In this study, we established a model to examine the biological basis for how paternal aging affects specific traits in their offspring. First, we confirmed behavioral abnormalities in offspring derived from old male mice. Because several literatures have indicated age-associated DNA methylation changes in sperm as a possible risk for the health problem in offspring, comprehensive targeted DNA methylome analysis was carried out using young and old mice sperm. We found in old sperm 16 hypermethylated and 96 hypomethylated genome loci, in which REST-binding domain was enriched. This is of interest because REST can repress various genes related with autism and schizophrenia. These findings suggest a possibility that age-associated DNA methylation changes may cause deterioration of transcriptional regulation of target genes/loci during brain development. The offspring showed defects in isolation induced vocal communication, spatial learning, and sensorimotor gating function, but their social communication and repetitive behavior were comparable to those derived from young male mice in our behavior paradigms. We are now challenging to elucidate how DMRs in old sperm actually affect gene expression within the offspring’s brain during development. 2S1-2 Modulation of behavioral deficits in animal models of autism spectrum disorder with agmatine Young Shin Chan Department of Pharmacology, School of Medicine, Konkuk University Autism spectrum disorder (ASD) is characterized by two core domains of symptoms such as social communication deficits and restricted repetitive behavior. Multiplex of risk factors and a myriad array of complex symptoms make obtaining the appropriate therapeutic targets against the devastating disorder a formidable challenge. Based on excitatory-inhibitory neuronal imbalance (E/I imbalance) theory of ASD, we tested the possibility of using agmatine, an endogenous neuromodulator with antagonistic effects against glutamate receptors, as a potential therapeutic target for ASD. Treatment of agmatine effectively suppressed social behavioral deficits in prenatally VPA-injected animals, which is a versatile and widely used animal model of ASD. Agmatine also normalized hyperactivity, repetitive behavior and seizure susceptibility of VPA animal model. Administration of agmatine increased the level of agmatine in brain and modulation of agmatine break down also improved the social impairments and repetitive behaviors. As a molecular signaling signature, VPA animal model showed dysregulated phosphorylation of Erk1/2, which is normalized by agmatine administration. As a proof of concept for the role of altered E/I imbalance in the modulation of core symptoms of ASD, we found increased glutamatergic neuronal differentiation in VPA animal models as exemplified by increased expression of AMPA receptor subunits. Interestingly, administration of VPA to Cntnap2 KO mice, which is an ASD animal model with decreased AMPA receptor activity did not produce alterations in glutamate receptor level and behavioral deficits. These results suggest that modulating glutamatergic neural activity might provide plausible target of ASD therapeutics, in which agmatine would be a promising candidates. 2S1-3 Leveraging genetic rat models of intellectual and developmental disabilities for basic science and translational research Rodney C Samaco1,2 1BCM Intellectual and Developmental Disabilities Research Center (IDDRC)，2Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital Genetic mouse models of intellectual and developmental disabilities (IDD) have been instrumental in our understanding of the consequences associated with disease-causing human mutations. Neurobehavioral deficits are prominent in IDD, and the use of tools such as the laboratory mouse is one approach to identify potential therapies that may improve these impairments. However, given the concerns that findings from mouse models may not necessarily reflect changes that are relevant to the human condition, and the possibility that such models may be sub-optimal for translational studies, we set out to determine the extent to which genetic manipulation in a second mammalian rodent species, the laboratory rat, results in similar and/or different neurobehavioral and molecular deficits. The laboratory rat displays unique advantages for studying behavioral phenotypes including social and cognitive assessments. Using both conventional neurobehavioral assays and assays that are uniquely suited for studies in the rat, we found that several genetic rat models of IDD-related genes display phenotypes that are not completely consistent with reported findings in the mouse including abnormalities in social behavior, one primary endophenotype that is typically studied in rodent models given its significance to IDD. However, other neurobehavioral phenotypes and molecular alterations in rat models are indeed concordant with historical mouse model findings. Taken together, these studies underscore the value of genetic rat models as complementary tools to the existing repertoire of IDD animal models, and highlight the benefit of cross-species analyses in identifying preclinical outcome measures with potentially greater disease-relevance. 2S1-4 Spatiotemporal brain transcriptome architecture and application for disease model in marmosets Yasuhiro Go Department of Brain Sciences, Center for Novel Science Initiatives, National Institutes of Natural Sciences, Okazaki, Aichi, Japan Spatiotemporal transcriptome gene regulations are essential for the construction of brain structure and proper function. Comprehensive analyses of the dynamics and the architecture of transcriptome in the both wild and diseased animal models also lead to understanding the molecular causality of the human neuropsychiatric disease. Here we examine the spatiotemporal transcriptome dynamics using the common marmoset brain to identify the spatiotemporal-specific modulating genes. Currently our team has been doing the following studies, (i) the postnatal developing marmoset brain transcriptome (five postnatal stages) at macro-scale resolution (seven cortex regions of both cerebral hemispheres, thalamus, midbrain, cerebellum), (ii) the adult marmoset brain transcriptome at micro-scale resolution (a single layer of cells from five cortical regions, a single nucleus from three subcortical regions), and (iii) the wild and the autism model marmoset brain transcriptome in prefrontal regions. Through this study, we aim to identify the molecular dynamics and trajectories between proper and atypical brain gene expressional networks.