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Role of local interneurons in early cortical dysfunction in Shank3 KO mice

局部中间神经元在 Shank3 KO 小鼠早期皮质功能障碍中的作用

基本信息

批准号：
10741946
负责人：
Rui Peixoto
金额：
$ 43.73万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2025-08-14
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10741946
关键词：
Address Adult Affect Animals Anterior Autopsy Behavior Brain Cells Compensation Development Disease Early Intervention Electrophysiology (science)Epilepsy Etiology Excitatory Synapse Exhibits Fiber Fiber Optics Functional disorder Glutamates Hyperactivity Impairment Individual Interneuron function Interneurons Knockout Mice Label Mediating Morphology Mus Mutation Neurodevelopmental Disorder Neurons Parvalbumins Pattern Phenotype Photometry Physiological Play Population Predisposition Prefrontal Cortex Property Prophylactic treatment Proteins Role Scaffolding Protein Seizures Sensory Severities Social Interaction Somatosensory Cortex Somatostatin Standardization Symptoms Synapses Techniques Testing Therapeutic Viral Work autism spectrum disorder cingulate cortex critical period design epileptiform genetic approach genome-wide hippocampal pyramidal neuron improved individuals with autism spectrum disorder insight mouse model neural patterning novel novel therapeutic intervention optical fiber postnatal postnatal development postnatal period response risk variant therapeutically effective transcriptomics treatment planning two-photon

项目摘要

PROJECT SUMMARY Epilepsy and epileptiform patterns of neural activity are extremely prevalent in autism spectrum disorders (ASD) but the specific mechanisms underlying the emergence of cortical hyperactivity in these conditions remain largely unknown. Several physiological and morphological abnormalities in cortical GABAergic interneurons have been observed in both autistic individuals and mouse models of autism, suggesting that cortical interneuron dysfunction might be a critical factor underlying cortical activity imbalances in ASD. We have recently shown that mice with deletions in Shank3 exhibit cortical hyperactivity during early postnatal development. Loss of Shank3 results in reduced interneuron activity in response to sensory stimulation in adult stages, but whether similar phenotypes are present early in development, when cortical hyperactivity emerges, remains unknown. We hypothesize that loss of Shank3 and subsequent reduction of glutamatergic drive in cortical interneurons is a primary cause of early cortical hyperactivity in Shank3 KO mice. To test this hypothesis we will use whole-cell electrophysiology and 2-photon microcopy techniques optimized for studies in developing mice, and characterize the physiological properties of Shank3 KO cortical Parvalbumin (PV) and Somatostatin (SST)-positive interneurons, the two major populations of inhibitory interneurons. This effort will identify a potential primary pathophysiological abnormality underlying early cortical hyperactivity in ASD that will guide the development of new therapeutic strategies that restore optimal network function during critical periods of cortical development.

项目总结癫痫和癫痫样的神经活动模式在自闭症谱系障碍(Asd)中非常普遍。但是，在这些情况下出现皮质多动的具体机制在很大程度上仍然存在。未知。大脑皮层GABA能中间神经元的几种生理和形态异常在自闭症患者和自闭症小鼠模型中都观察到，这表明皮质中间神经元功能障碍可能是ASD皮质活动失衡的关键因素。我们最近已经证明， Shank3基因缺失的小鼠在出生后早期表现出皮质功能亢进。Shank3的损失导致成年阶段对感觉刺激反应的中间神经元活性降低，但是否相似表型存在于发育的早期，当皮质多动出现时，仍不清楚。我们假设Shank3的缺失和随后皮质中间神经元谷氨酸能驱动的减少是一种 Shank3KO小鼠早期皮质过度活动的主要原因。为了验证这一假设，我们将使用全细胞电生理学和双光子显微技术优化了发育中小鼠的研究，并表征了 Shank3KO皮质小白蛋白和生长抑素阳性的生理特性中间神经元是抑制性中间神经元的两大类群。这项工作将确定一个潜在的初选 ASD早期皮质过度活动的病理生理异常将指导在皮质发育的关键时期恢复最佳网络功能的新治疗策略。