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

项目摘要 癫痫和癫痫样神经活动模式在自闭症谱系障碍（ASD）中非常普遍 但在这些条件下出现皮质过度活跃的具体机制仍然主要是 未知皮质GABA能中间神经元的几种生理和形态学异常已经被发现。 在自闭症个体和自闭症小鼠模型中观察到，这表明皮质中间神经元 功能障碍可能是ASD中皮质活动失衡的关键因素。我们最近的研究表明 Shank3缺失的小鼠在出生后早期发育过程中表现出皮质活动过度。失去柄3 在成年阶段，对感觉刺激的反应导致中间神经元活动减少，但是否相似 表型存在于发育的早期，当皮质过度活跃出现时，仍然未知。我们 假设皮层中间神经元中Shank3缺失和随后的多巴胺能驱动的减少是 Shank3 KO小鼠早期皮质活动过度的主要原因。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镜技术，优化了发育中小鼠的研究，并表征 Shank3 KO皮质小清蛋白（PV）和生长抑素（SST）阳性的生理特性 中间神经元，抑制性中间神经元的两个主要群体。这项工作将确定一个潜在的主要 ASD早期皮质功能亢进的病理生理学异常将指导 新的治疗策略，在皮质发育的关键时期恢复最佳网络功能。

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.