Investigating a novel mechanism underlying prefrontal cortex dysfunction in autism and intellectual disability

研究自闭症和智障患者前额叶皮质功能障碍的新机制 残障“ 项目摘要/摘要 自闭症谱系障碍和智力障碍是两种普遍存在的神经发育障碍，它们是 经常同时诊断(ASD/ID)。较高水平的认知处理困难，包括注意力， 记忆和社会互动是ASD/ID的标志。认知障碍被认为是由于突触 前额叶皮质(PFC)功能障碍，尽管PFC突触损伤背后的机制主要是 未知。来自几个大规模遗传分析的融合证据已经确定了ADNP，编码一种 神经元染色质重构体，作为ASD/ID的首要风险基因。初步数据显示，ADNP在 自闭症患者的PFC。该项目使用基于病毒的基因转移来击倒(KD)ADNP。 探讨ADNP缺乏症的分子基础。对事件的初步调查 ADNP KD的作用表现为认知行为障碍和谷氨酸能突触缺陷。 转录分析显示与小胶质细胞介导的炎症相关的基因转录上调， 这反映了人类ASD/ID的小胶质细胞上调的结果。小胶质细胞是微调突触所必需的 PFC的发育，但过度激活会损害周围神经元。基于这些发现，这 该提案旨在研究ASD/ID患者PFC功能障碍背后的一种新机制。 假设促炎转录的增加是由于ADNP介导的基因丢失 神经元中的抑制作用。因此，小胶质细胞激活增加会导致过度的突触丢失，从而导致 观察到突触损伤。为了验证这一点，ADNP对小胶质细胞中介因子的转录控制 将在ADNP KD(目标1)中进行调查。小胶质细胞消融将应用于ADNP KD以评估 小胶质细胞对PFC突触功能的影响(目标2)。从这项研究中获得的结果将为 基于PFC的ASD/ID认知症状的新治疗策略。这项工作将在 纽约州立大学布法罗分校在我的赞助人纽约州立大学纽约分校博士甄燕的实验室里 在ASD/ID和表观遗传调控方面有专长的杰出教授。以补充我的过渡到 作为一名独立科学家，该奖学金的培训计划重点是掌握新的实验技术， 科学交流，实验设计和严谨，教学和领导。作为一名未来的医生- 科学家，我还和我的临床导师制定了相邻的培训计划，旨在 向我介绍临床儿童精神病学，并在这个阶段帮助我整合临床和研究经验 我职业生涯的一部分。

“Investigating a novel mechanism underlying prefrontal cortex dysfunction in autism and intellectual disability” Project Summary / Abstract Autism spectrum disorder and intellectual disability are two prevalent neurodevelopmental disorders which are frequently diagnosed concurrently (ASD/ID). Difficulty with higher-level cognitive processing, including attention, memory, and social interaction, is the hallmark of ASD/ID. Cognitive impairment is thought to be due to synaptic dysfunction in the prefrontal cortex (PFC), though the mechanisms behind PFC synaptic impairment are largely unknown. Converging evidence from several large-scale genetic analyses has identified ADNP, encoding a neuronal chromatin remodeler, as a top risk gene for ASD/ID. Preliminary data shows that ADNP is reduced in the PFC of patients with autism. This project employs viral-based gene transfer to knock down (KD) Adnp in mouse PFC neurons to investigate the molecular underpinnings of ADNP deficiency. Initial investigation into the effects of ADNP KD demonstrated cognitive behavioral impairment and glutamatergic synaptic deficits. Transcriptomic analysis revealed upregulation of gene transcripts related to microglia-mediated inflammation, which mirrors findings of microglial upregulation in human ASD/ID. Microglia are essential for fine-tuned synaptic development in the PFC, but excess activation can damage surrounding neurons. Based on these findings, this proposal intends to investigate a novel mechanism behind the PFC dysfunction in ASD/ID. The working hypothesis is that the increase in pro-inflammatory transcription is due to loss of ADNP-mediated gene repression in neurons. Consequently, increased microglial activation causes excess synaptic loss, leading to the observed synaptic impairment. To test this, the transcriptional control of ADNP on microglia-mediating factors will be investigated in Adnp KD (Aim 1). Microglial ablation will be employed in ADNP KD to evaluate the influence of microglia on PFC synaptic function (Aim 2). Results gained from this study will provide insights into novel therapeutic strategies for the PFC-based cognitive symptomatology of ASD/ID. This work will be done at the State University of New York at Buffalo in the laboratory of my Sponsor Zhen Yan, PhD, a SUNY Distinguished Professor with expertise in ASD/ID and epigenetic modulation. To supplement my transition into an independent scientist, the training plan for this fellowship focuses on mastering new experimental techniques, scientific communication, experimental design and rigor, and teaching and leadership. As a future physician- scientist, I have additionally formulated an adjacent training plan with my clinical mentor, which is designed to introduce me to clinical child psychiatry and help me to integrate clinical and research experience at this stage of my career.