Mechanisms and pathogenic role of early corticostriatal dysfunction in Shank3B-/- mice

项目总结 尽管对自闭症风险的遗传基础的了解越来越多，但具体的致病机制 自闭症谱系障碍(ASD)中出现运动和认知障碍的潜在原因尚不清楚。 最近的成像和遗传学研究指出，皮质纹状体功能障碍是一种普遍的病理生理机制。 在ASD中。尤其是前额叶皮质(PFC)肥大和功能连接异常。 背内侧纹状体(DMS)已在多个自闭症患者中被报道，提供了潜在的 与自闭症相关的重复行为和社会缺陷的神经病理基础。我们的 实验室已经表明，具有功能缺失的小鼠在SHANK3(Shank3B-/-)，一种高度渗透性 孤独症的单基因病因，表现为皮质纹状体回路的多动和连接异常模式 在出生后发育过程中。这些动物的行为缺陷也会在这些早期出现 发育阶段，提示早期皮质纹状体功能障碍可能是一个重要的致病因素 SHANK3相关疾病的发病机制。在这里，我们建议进一步描述纹状体回路是如何 Shank3的缺失损害了发育，并确定了在这些过程中受影响的特定皮质纹状体通路 条件(Aim1)。此外，使用最近开发的条件转基因小鼠，允许细胞特异性 操纵Shank3的表达，我们将剖析导致皮质纹状体的具体机制 连接异常(目标2)。此外，使用新的分子策略使早期兴奋正常化 驱动纹状体神经元，我们将确定早期纹状体回路功能障碍在 Shank3B-/-小鼠出现不适应行为(目标3)。这项工作将增进我们对 调节皮质纹状体回路成熟的基本机制和发育规律 对ASD和其他早期活动的神经发育障碍发病机制的重要见解 皮质纹状体回路的失衡。

PROJECT SUMMARY Despite increasing knowledge of the genetic underpinnings of autism risk, the specific pathogenic mechanisms underlying the emergence of motor and cognitive deficits in autism spectrum disorders (ASD) remain unclear. Recent imaging and genetic studies have pointed to corticostriatal dysfunction has a prevalent pathophysiology in ASD. In particular, hypertrophy and abnormal functional connectivity of prefrontal cortex (PFC) and dorsomedial striatum (DMS) have been reported in multiple autistic individuals, providing a potential neuropathological substrate for the repetitive behaviors and social deficits associated with autism. Our laboratory has shown that mice with loss of function deletions in SHANK3 (Shank3B-/-), a highly penetrant monogenic cause of autism, exhibit hyperactivity and abnormal patterns of connectivity in corticostriatal circuits during postnatal development. Behavioral deficits in these animals also emerge during these early developmental periods, suggesting that early corticostriatal dysfunction might be an important pathogenic mechanism in SHANK3 associated disorders. Here we propose to further characterize how striatal circuit development is impaired by loss of Shank3 and identify the specific corticostriatal pathways affected in these conditions (Aim1). In addition, using recently developed conditional transgenic mice that allow cell-specific manipulation of Shank3 expression we will dissect the specific mechanisms leading to corticostriatal connectivity abnormalities (Aim 2). In addition, using new molecular strategies that normalize early excitatory drive in striatal neurons, we will determine the pathogenic role of early striatal circuit dysfunction in the emergence of maladaptive behaviors in Shank3B-/- mice (Aim 3). This work will advance our understanding of the basic mechanisms and developmental rules regulating the maturation of corticostriatal circuits and provide important insights into the pathogenesis of ASD and other neurodevelopmental disorders with early activity imbalances in corticostriatal circuits.