Molecular Neurobiology of Schizophrenia
JS4-2-1-1 Patho-physiological functions of DISC1, a susceptibility gene of schizophrenia ○貝淵弘三1 ○Kozo Kaibuchi1 名古屋大学大学院医学系研究科1 Nagoya University, Graduate School of Medicine1 Disrupted-In-Schizophrenia 1 (DISC1) is a promising candidate gene for susceptibility to psychiatric disorders, including schizophrenia. DISC1 appears to be involved in neurogenesis, neuronal migration, axon/dendrite formation and synapse formation; during these processes, DISC1 acts as a scaffold protein by interacting with various partners. However, the lack of DISC1 knockout mice and a well-characterized antibody to DISC1 has made it difficult to determine the exact role of DISC1 in vivo. We have recently generated mice lacking exons 2 and 3 of the Disc1 gene and prepared specific antibodies to the N- and C-termini of DISC1. The DISC1 knockout mice are viable and fertile, and no gross phenotypes, such as disorganization of the brain's cytoarchitecture, are observed. The DISC1-specific antibodies recognize a protein with an apparent molecular mass of ~100 kDa in brain extracts from wild-type mice but not in brain extracts from DISC1 mutant mice. DISC1 is mainly localized to the vesicles associated with the Golgi apparatus and microtubules in hippocampal neurons and astrocytes. A deficiency of full-length Disc1 induces a threshold shift in the induction of long-term potentiation in the dentate gyrus. The Disc1 knockout mice displays abnormal emotional behavior as assessed by the elevated plus-maze and cliff-avoidance tests, thereby suggesting that a deficiency of full-length DISC1 may result in lower anxiety and/or higher impulsivity. By using the Disc1 knockout mice, we have found that DISC1 acts as a cargo adapter for neuronal transport of specific proteins and mRNAs. We discuss the patho-physiological functions of DISC1, which are re-evaluated by the DISC1 knockout mice and the well-characterized antibodies, in the symposium.	JS4-2-1-2 Cytokine Hypothesis for Schizophrenia; Implication of Abnormal ErbB signaling Cytokine Hypothesis for Schizophrenia; Implication of Abnormal ErbB signaling ○那波宏之1 ○Hiroyuki Nawa1 新潟大学脳研究所基礎神経科学部門分子神経生物学1 Dept. Mol. Neurobiol. Brain Res. Inst., Niigata Univ.1 Schizophrenia is thought to be the psychiatric disorder of developmental origin that involves both environmental factors and genetic factors to impair neural differentiation or maturation. Genetic and postmortem studies have identified two cytokines, neuregulin-1 (NRG1) and epidermal growth factor (EGF), as risk molecules for this illness. Both NRG1 and EGF act on ErbB receptors to regulate the development of GABAergic and dopaminergic neurons and myelination, whose abnormalities are often reported in schizophrenia neuropathology. In agreement, our animal modeling studies indicate that these two cytokines produce the most remarkable impact on animal behaviors relevant to schizophrenia among the fourteen cytokines we have ever tested. The mice, rats and monkeys that exposed to these cytokines as neonates all develop cognitive/behavioral abnormality at post-pubertal stages without apparent learning deficits. In addition, these animals exhibit cerebroventricular enlargement as well as higher sensitivity to the psychostimulants. Of notes, EGF and NRG1 are also encoded by pox viruses and, even in the case of other viruses, viral genome (i.e, poly I:C) evokes EGF/NRG1 signals by transactivation. Thus, these cytokine signals can be implicated in the maternal viral infection for schizophrenia etiology. The validity and discrepancy of this cytokine hypothesis will be discussed further.
JS4-2-1-3 Glutamate Circuit Dysfunction and Schizophrenia: Insights from Ketamine ○John H. Krystal1,2,3, Alan Anticevic1,2,3, Phillip Corlett1,2,3, Naomi Driesen1,2,3, John Murray1,2,3, Xiao-Jing Wang1,2,3 Department of Psychiatry, Yale University School of Medicine, New Haven, USA1, Yale-New Haven Hospital, New Haven, USA2, VA Connecticut Healthcare System, West Haven, USA3 The purpose of this presentation is to share results emerging from psychopharmacology, brain imaging, and computational neuroscience studies exploring the extent of the convergence of the circuit dysfunction arising from the administration of NMDA glutamate receptor antagonists to animals and humans and findings in schizophrenia patients. Building on an earlier literature, studies beginning in our laboratory described similarities between the behavioral effects of ketamine and clinical findings in schizophrenia. This presentation will explore three central issues: 1) both ketamine effects in healthy humans and schizophrenia are associated with impaired prefrontal cortical activation associated with the encoding/early maintenance phase of working memory, a finding attributed to impaired recurrent excitation within the cortex; 2) both ketamine effects in healthy humans and schizophrenia are associated with impaired inhibitory tuning of activity within working memory networks, associated with deficient cortical inhibition during working memory, reduced precision of working memory, and reduced antagonism between the "executive" and "default" large scale networks; however, 3) ketamine produced increased global functional connectivity and increased resting cortical gamma oscillations in cortical networks at rest, whereas schizophrenia is associated with reduced global functional connectivity and perhaps increased gamma oscillations at rest, differences that has been hypothesized to arise from differences in GABA neuronal populations modulated by ketamine and affected by schizophrenia. These findings suggest that schizophrenia might be treated, in part, by drugs that restore or normalize glutamate synaptic function in recurrent excitatory networks, restore inhibitory tuning, or normalize synchrony within cortical networks.	JS4-2-1-4 Translational models of NMDA receptor dysfunction in Schizopherenia ○Daniel Javitt1, 2, 3 Columbia Conte Center for Schizophrenia Research, New York, USA1, Psychiatry and Neuroscience, Columbia University College of Physicians and Surgeons, New York, USA2, Division of Schizophrenia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg3

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