Olfactory Evoked Potentials and Developmental Neuropathology in Schizophrenia

描述（由申请人提供）：在感觉方式中，嗅觉与精神分裂症病理学中最常涉及的颞叶边缘和额叶区域最密切相关。因此，嗅觉探针可能是理想的工具，以评估这些神经基板的结构和功能的完整性。在精神分裂症患者外周感觉传入神经被破坏的程度上，嗅觉系统--由于其战略性的解剖位置--也可能特别容易受到破坏。因此，嗅觉功能障碍可能是精神分裂症病理学的一个敏感指标，甚至可能作为疾病脆弱性或发病的“早期预警”信号。此外，由于神经发生和神经发育持续一生中的嗅神经上皮和嗅球（OB），嗅觉系统的探针可以提供洞察异常神经发育的神经生物学基础。这个项目，现在在其第11个年头，代表了唯一的系统性努力，从神经生物学，而不是一个简单的行为，角度来描述精神分裂症的嗅觉缺陷。最近的研究已经确定了特定的异常，涉及异常G蛋白介导的信号转导在外周嗅觉受体神经元（ORN）和改变ORN和嗅球之间的突触连接作为特定的神经发育机制，可能会被破坏。这一更新申请提出了一个独特的体内-体外翻译研究这些异常。将在35名成年精神分裂症患者、35名有精神分裂症遗传风险的青少年、35名有前驱症状的临床风险青少年和适当年龄匹配的对照组中对外周嗅觉系统（包括上皮和初级感觉皮层反应）进行详细的行为和电生理研究。嗅觉上皮活检组织将从精神分裂症患者和年龄匹配的对照组获得。作为再生神经细胞的唯一来源，嗅觉上皮活检提供了一个无与伦比的机会，直接评估神经元的完整性在一个活着的人。上皮活检组织，沿着与嗅球从死后材料中获得，将用于研究细胞和分子机制，在体内观察到的失调。一个特别的焦点将是G蛋白介导的细胞内信号转导和ORN-OB突触连接。总体假设是嗅觉缺陷反映了遗传介导的细胞内信号传导和神经元-神经元连接的异常，这些异常是由神经发生和突触形成的发育紊乱过程引起的。

DESCRIPTION (provided by applicant): Among the sensory modalities, olfaction is most closely associated with the temporo-limbic and frontal regions most commonly implicated in schizophrenia pathology. Olfactory probes may therefore be ideal tools to assess the structural and functional integrity of these neural substrates. To the extent that peripheral sensory afferents are disrupted in schizophrenia, the olfactory system - owing to its strategic anatomic location - may also be especially vulnerable to disruption. So, olfactory dysfunction may be a sensitive indicator of schizophrenia pathology, and may even serve as an "early warning" sign of disease vulnerability or onset. In addition, since neurogenesis and neurodevelopment persist throughout life in the olfactory neuro-epithelium and the olfactory bulb (OB), probes of the olfactory system may provide insight into the neurobiological basis of aberrant neurodevelopment. This project, now in its eleventh year, represents one of the only systematic efforts to characterize schizophrenia olfactory deficits from a neurobiological, rather than a simply behavioral, perspective. Recent studies have identified specific abnormalities implicating abnormal G protein-mediated signal transduction in peripheral olfactory receptor neurons (ORNs) and altered synaptic connectivity between ORNs and olfactory bulb as specific neurodevelopmental mechanisms that may be disrupted. This renewal application proposes a unique in vivo - in vitro translational investigation of these abnormalities. Detailed behavioral and electrophysiological studies of the peripheral olfactory system, including both epithelial and primary sensory cortical responses, will be conducted in 35 adult schizophrenia patients, 35 adolescents with a genetic risk for schizophrenia, 35 clinical-risk adolescents with prodromal symptoms, and appropriate age- matched control groups. Olfactory epithelial biopsy tissue will be acquired from the schizophrenia patients and age-matched controls. As the only accessible source of regenerating neural cells, olfactory epithelial biopsy offers an unparalleled opportunity to directly assess neuronal integrity in a living human. The epithelial biopsy tissue, along with olfactory bulbs obtained from post-mortem material, will used to investigate the cellular and molecular mechanisms that underlie the dysregulations observed in vivo. A particular focus will be G protein- mediated intracellular signal transduction and ORN-OB synaptic connectivity. The overarching hypothesis is that olfactory deficits reflect genetically-mediated abnormalities in intracellular signaling and neuron-to-neuron connectivity, which arise from developmentally disturbed processes of neurogenesis and synapse formation.