Uncovering the role of SAP97 in synaptic function and schizophrenia.

揭示 SAP97 在突触功能和精神分裂症中的作用。

• 批准号: 10736790
• 负责人: Bruce Herring
• 金额: $ 45.13万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736790
• 关键词: 3q29; AMPA Receptors; Affect; Alternative Splicing; Alzheimer' s Disease; Animal Behavior; Animals; Antibodies; Behavior; Behavioral; Binding; Biological; Brain; Brain Diseases; Brain region; Clinical Data; Complex; Cytoplasmic Granules; DLG1 gene; Data; Dendrites; Development; Disease; Distal; Electrophysiology (science); Endoscopy; Episodic memory; Etiology; Exhibits; Functional disorder; Gene Expression; Genes; Genetic; Glutamates; Goals; Hippocampus; Human; Human Genetics; Imaging Device; Individual; Knowledge; Label; Laboratories; Lateral; Lead; Link; Medial; Memory; Mental disorders; Methods; Missense Mutation; Mission; Molecular; National Institute of Neurological Disorders and Stroke; Neurons; Pathologic; Pathology; Pathway interactions; Perforant Pathway; Play; Property; Protein Isoforms; Public Health; Reagent; Regulation; Research; Rodent; Rodent Model; Role; Schizophrenia; Severities; Specificity; Symptoms; Synapses; Techniques; Testing; Time; Variant; Work; autism spectrum disorder; dentate gyrus; genetic regulatory protein; high risk; hippocampal pyramidal neuron; imaging approach; immunoreactivity; in vivo; in vivo imaging; information processing; innovation; microdeletion; neurotransmission; novel therapeutic intervention; pre-clinical; response; schizophrenia risk; synaptic function; tool; trafficking; transmission process

PROJECT SUMMARY Preclinical and clinical data show elevated glutamatergic transmission and neuronal activity within the hippocampus during the early stages of schizophrenia development, and it is proposed that such elevations drive the progression of the disorder. However, the molecular and cellular mechanisms that give rise to schizophrenia- related elevations in hippocampal glutamatergic transmission are unknown. Recent human genetic data supports a connection between reduced DLG1 gene expression/function and schizophrenia. The DLG1 gene encodes the putative synaptic regulatory protein SAP97. However, a clear synaptic regulatory role for SAP97 has remained elusive. We have now, for the first time, identified a native synapse in the brain where SAP97 plays a critical and direct role in synaptic regulation. The long-term goal of our research is to understand how glutamatergic synapse dysfunction contributes to the development of psychiatric disorders. Our central hypothesis is that disruption of SAP97 function in dentate granule neurons (DG neurons) of the hippocampus produces pathological synaptic strengthening that contributes to schizophrenia etiology. Guided by strong preliminary data, we will pursue this hypothesis in three specific aims. In Aim 1, we will combine electrophysiological methods with brand new imaging tools to characterize pathway-specific roles of SAP97 in regulating glutamatergic neurotransmission and plasticity. In Aim 2, we will use a combination of newly generated antibodies, molecular biological and electrophysiological/imaging approaches to identify the roles of SAP97 subregions in governing SAP97’s subcellular localization and influence over glutamatergic synapse function in DG neurons. In Aim 3, we will deploy cutting-edge in vivo imaging tools in freely behaving animals in order to understand how hippocampal neuron activity is altered in rodents with compromised SAP97 function. The present proposal is innovative because it deploys new and powerful genetic, in vivo imaging, and behavioral analysis tools that will allow a precise characterization of a newly discovered role for SAP97 in regulating the function of native glutamatergic synapses in the hippocampus. The proposal is significant because it stands to identify synaptic pathology in a specific brain region that represents a common component in schizophrenia development. This proposal squarely meets the mission objectives of the NINDS given its focus on understanding glutamatergic synapse regulation and memory formation which are found to be disrupted in complex brain disorders.

项目摘要 临床前和临床数据显示，在神经元内， 海马在精神分裂症发展的早期阶段，并提出，这种海拔驱动 疾病的发展然而，导致精神分裂症的分子和细胞机制- 海马神经元能传递的相关升高尚不清楚。最近的人类基因数据支持 DLG 1基因表达/功能降低与精神分裂症之间的联系。DLG 1基因编码 突触调节蛋白SAP 97然而，SAP 97明确的突触调节作用， 仍然难以捉摸我们现在已经首次确定了大脑中的一个天然突触，SAP 97在其中发挥作用。 在突触调节中起着重要而直接的作用。我们研究的长期目标是了解 神经元突触功能障碍有助于精神疾病的发展。我们的中央 假设是海马齿状颗粒神经元（DG神经元）中SAP 97功能的破坏 产生病理性突触强化，导致精神分裂症的病因。以强为导 根据初步数据，我们将在三个具体目标中继续这一假设。在目标1中，我们将联合收割机 电生理学方法与全新的成像工具，以表征SAP 97的通路特异性作用， 调节神经递质和可塑性。在目标2中，我们将使用新生成的 抗体、分子生物学和电生理学/成像方法来鉴定SAP 97的作用 调控SAP 97亚细胞定位的亚区及其对突触功能的影响 DG神经元。在目标3中，我们将在自由行为的动物中部署尖端的体内成像工具， 了解SAP 97功能受损的啮齿动物中海马神经元活动如何改变。的 目前的建议是创新的，因为它部署了新的和强大的遗传，体内成像，和行为 分析工具，将允许精确表征新发现的作用SAP 97在调节 海马体中的天然突触的功能。这项建议意义重大，因为它表明， 识别代表精神分裂症常见成分的特定脑区中的突触病理 发展该建议完全符合NINDS的使命目标，因为其重点是 理解神经元突触调节和记忆形成，发现这些在 复杂的脑部疾病