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

“研究自闭症和智力障碍患者前额皮质功能障碍的一种新机制， 残疾” 项目总结/摘要 自闭症谱系障碍和智力残疾是两种常见的神经发育障碍， 经常同时诊断（ASD/ID）。高级认知处理困难，包括注意力， 记忆和社会交往是ASD/ID的标志。认知障碍被认为是由于突触 前额叶皮层（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证据已经确定了ADNP，编码一种 神经元染色质重塑，作为ASD/ID的最高风险基因。初步数据显示， 自闭症患者的前额叶皮层该项目采用基于病毒的基因转移来敲低（KD）Adnp， 小鼠PFC神经元研究ADNP缺乏的分子基础。初步调查 ADNP KD的作用表现为认知行为障碍和神经元能突触缺陷。 转录组学分析揭示了与小胶质细胞介导的炎症相关的基因转录物的上调， 这反映了人类ASD/ID中小胶质细胞上调的发现。 在PFC的发展，但过度激活会损害周围的神经元。根据这些发现， 该提案旨在研究ASD/ID中PFC功能障碍背后的新机制。 一种假说认为，促炎转录的增加是由于ADNP介导的基因的丢失 神经元的抑制因此，增加的小胶质细胞活化引起过度的突触损失，导致神经胶质细胞损伤。 观察到突触损伤。为了验证这一点，研究了ADNP对小胶质细胞介导因子的转录调控， 将在Adnp KD（目标1）中进行研究。将在ADNP KD中采用小胶质细胞消融术以评估 小胶质细胞对PFC突触功能影响（目的2）。从这项研究中获得的结果将提供深入了解 基于PFC的ASD/ID认知障碍学的新治疗策略。这项工作将在 在布法罗的纽约的州立大学的实验室里，我的赞助人Zhen Yan博士，一个SUNY 杰出教授，在ASD/ID和表观遗传调节方面具有专业知识。为了补充我的过渡到 作为一名独立的科学家，该奖学金的培训计划侧重于掌握新的实验技术， 科学交流，实验设计和严谨性，以及教学和领导力。作为未来的医生- 作为一名科学家，我还与我的临床导师制定了一个相邻的培训计划，旨在 向我介绍临床儿童精神病学，并帮助我在现阶段整合临床和研究经验 我的职业生涯。

“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.