Olfactory Evoked Potentials and Developmental Neuropathology in Schizophrenia

描述(申请人提供)：在感觉模式中，嗅觉与精神分裂症病理中最常见的颞叶边缘和额叶区域关系最密切。因此，嗅觉探头可能是评估这些神经基质结构和功能完整性的理想工具。在精神分裂症患者的外周感觉传入受到干扰的程度上，嗅觉系统--由于其具有战略意义的解剖位置--也可能特别容易受到干扰。因此，嗅觉障碍可能是精神分裂症病理的一个敏感指标，甚至可以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贯穿于嗅神经上皮和嗅球(OB)的整个生命过程，嗅觉系统的探测可能提供对神经发育异常的神经生物学基础的洞察。这个项目，现在已经进入第11个年头，代表着仅有的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系统性努力之一。最近的研究发现，外周嗅觉感受器神经元G蛋白介导的信号转导异常和嗅球与嗅球之间突触连接的改变是可能被破坏的特定神经发育机制。这一更新应用提出了一种对这些异常的独特的体内-体外翻译研究。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以及适当的年龄匹配的对照组中，对外围嗅觉系统进行详细的行为和电生理研究，包括上皮和初级感觉皮质反应。嗅觉上皮活检组织取自精神分裂症患者和年龄匹配的对照组。作为再生神经细胞的唯一来源，嗅觉上皮活组织检查提供了一个无与伦比的机会，可以直接评估活人神经元的完整性。上皮活检组织，以及从尸检材料中获得的嗅球，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。最重要的假设是，嗅觉缺陷反映了遗传介导的细胞内信号和神经元到神经元连接的异常，这些异常是由神经发生和突触形成的发育障碍过程引起的。 公共卫生相关性：精神分裂症是一种复杂的遗传疾病，大脑结构和功能的早期发育异常对于确定疾病的易感性非常重要。在不同的感官中，嗅觉与与疾病有关的大脑区域关系最密切。因此，嗅觉异常可能是疾病发病的“早期预警信号”。这项研究将检查精神分裂症患者和有患病风险的青少年对气味的神经反应的变化。这些异常的分子原因将用嗅觉上皮活组织和死后嗅球组织来研究。这可能会对精神分裂症的发展原因提供重要的见解，并有助于早期干预或预防。

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.