Sunday, May 11, 2025
5/11/2025
Investigating a novel mechanism underlying prefrontal cortex dysfunction in autism and intellectual disability - “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.
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