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Morphological analysis of synaptic pathophysiology of Schizophrenia-model mice: The discovery of huge spines
統合失調症モデルのシナプス病態の形態学的解析：巨大シナプスの発見
Shirai Fukutoshi（白井 福寿）1,2，小尾 紀翔2，鈴木 紀光2，林（高木） 朗子2
1Laboratory of Structural Physiology, CDBIM, The University of Tokyo
2Laboratory of Medical Neuroscience, IMCR, Gunma University
Schizophrenia (SZ) is a devastating mental disorder with a strong genetic predisposition, and its onset is often late adolescence. Although the pathogenesis of the disease remains elusive, the studies with the postmortem brain and human brain imaging have repeatedly reported the involvement of the synapse as the pathophysiology of this disease. Furthermore, it is noted that the products of the susceptibility genes for SZ are significantly accumulated in the glutamatergic synapse, among which DISC1, one of a strong candidate gene for SZ, functions a hub factor that regulates the postsynaptic glutamatergic signaling. However, the function of synapse in the pathophysiology of SZ remains entirely unknown. We, therefore, investigated and compared the synaptic phenotype in two independent rodent models: the conventional Disc1 knockdown(KD) and the Calcineurin knockout mice. Through the analyses, we found the significantly increased probability of the huge dendritic spine in the prefrontal cortex of both two models. The presence of the huge spine in the two models made us to hypothesize that the huge spine can be are common and key phenotype of SZ pathophysiology. Since there is a strong positive correlation among the spine head size and the amplitude of EPSCs, we hypothesized that excess current generated by the huge spine could disturb dendritic computation and neural firing. To investigate the importance of this phenotype, we generated conditional Disc1 KD mice which is suited for investigating the effect of the huge spine on neural event and behavior. And we found conditional knockdown of disc1 gene also induces increased spine head size by morphological analysis. Now we are performing behavioral and electrophysiological analysis to investigate the detail features of it. | | WD6-2
VPAC2 receptor overactivation implicated in schizophrenia susceptibility causes alterations in dendritic morphology of cortical neurons and cognitive impairments in mice
統合失調症の発症脆弱性因子としてのVPAC2受容体過活性化による大脳皮質神経発達異常と認知機能障害の発現
Takeuchi Shuto（竹内 修斗）1，山内 良介1，河内 琢也1，早田 敦子1,2，Waschek James3，橋本 均1,2,4，吾郷 由希夫5
1Lab. of Mol. Neuropharmacol., Grad. Sch. of Pharmaceut. Sci., Osaka Univ., Suita/Osaka, Japan
2United Grad. Sch. of Child Dev., Osaka Univ., Suita/Osaka, Japan
3Dept. of Psychiatry, Univ. of California Los Angeles, CA, USA
4Inst. for Datability Sci., Osaka Univ., Suita/Osaka, Japan
5Lab. of Biopharmaceutics, Grad. Sch. of Pharmaceut. Sci., Osaka Univ., Suita/Osaka, Japan
Rare microduplications at 7q36.3, containing VIPR2, have been known to confer a risk for schizophrenia. VIPR2 encodes the VPAC2 receptor that binds two homologous neuropeptides, VIP and PACAP. Lymphocytes from patients with these microduplications exhibited higher VIPR2 gene expression and VIP responsiveness, but mechanisms by which overactive VPAC2 signaling may lead to psychiatric disorders are unknown. Here we aimed to determine if the VIPR2-linkage to mental health disorders might be due to overactive VPAC2 receptor signaling during early neurodevelopment by daily administration of the selective VPAC2 receptor agonist Ro25-1553 from postnatal day 1 (P1) to P14 in mice. Western blot analyses on P21 revealed significant reductions of synaptophysin and PSD-95 in the prefrontal cortex, but not in the hippocampus, in Ro25-1553-treated mice. Golgi staining in adult brain revealed alterations in dendritic morphology of prefrontal and perirhinal cortical neurons in Ro25-1553-treated mice. The same postnatally-restricted treatment resulted in cognitive impairments in the novel object recognition and social recognition tests. Chronic treatment with clozapine, an atypical antipsychotic drug, ameliorated these behavioral and neuroanatomical abnormalities. Additionally, Ro25-1553 caused reductions in total numbers and length of neuronal dendrites and length of axon in primary mouse cortical neurons, and the effects were abolished in VPAC2 receptor-deficient mice. These findings implicate a potential pathological role of VPAC2 receptor overactivation, providing the hypothesis that VIPR2 duplications increase the risk of schizophrenia partly due to deficits in neuronal maturation by overactivation of VPAC2 signaling at a critical stage of brain development. |
