Olfactory Evoked Potentials and Developmental Neuropathology in Schizophrenia

描述（由申请人提供）：在感觉方式中，嗅觉与颞叶边缘和额叶区域最密切相关，最常涉及精神分裂症病理。因此，嗅觉探针可能是评估这些神经基质结构和功能完整性的理想工具。在某种程度上，精神分裂症患者的外周感觉传入被破坏，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的一个敏感指标，甚至可能作为疾病易感性或发病的“早期预警”信号。此外，由于神经发生和神经发育在嗅神经上皮和嗅球（OB）的整个生命中持续存在，嗅觉系统的探针可能提供对异常神经发育的神经生物学基础的见解。这个项目现在已经进入了第11个年头，它代表了从神经生物学而不是简单的行为角度来描述精神分裂症嗅觉缺陷的唯一系统努力之一。最近的研究发现，外周嗅觉受体神经元（orn）中G蛋白介导的异常信号转导以及orn与嗅球之间突触连通性的改变是可能被破坏的特定神经发育机制。这个更新的应用程序提出了一个独特的体内-体外翻译研究这些异常。研究人员将对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以及年龄匹配的对照组进行详细的外周嗅觉系统行为和电生理研究，包括上皮和初级感觉皮质反应。将从精神分裂症患者和年龄匹配的对照组中获得嗅上皮活检组织。作为再生神经细胞的唯一来源，嗅上皮活检提供了一个无与伦比的机会来直接评估活体神经细胞的完整性。上皮活检组织，以及从死后材料中获得的嗅球，将用于研究体内观察到的失调的细胞和分子机制。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。总的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间连接异常，这是由神经发生和突触形成的发育障碍过程引起的。

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. PUBLIC HEALTH RELEVANCE: Schizophrenia is a complex genetic disorder, with early developmental abnormalities in brain structure and function being important in determining vulnerability to illness. Among the different senses, olfaction is most closely associated with the brain regions implicated in the illness. Smell abnormalities may therefore be an "early warning sign" of disease onset. This study will examine changes in neural responses to odors in schizophrenia patients and adolescents who are at risk for the illness. The molecular causes of these abnormalities will be studied using both olfactory epithelial biopsies and post-mortem olfactory bulb tissue. This may provide important insights into the developmental causes of schizophrenia and facilitate early intervention or prevention.