Northwestern Events Calendar

May
19
2022

Center for Autism and Neurodevelopment seminar - Ted Abel, PhD, "Genetic Vulnerability of Striatal Networks as a Core Mechanism Underlying Neurodevelopmental Disorders"

When: Thursday, May 19, 2022
2:00 PM - 3:00 PM Central

Where: Ward Building, 5th floor, Room 5-230, 303 E. Chicago Avenue, Chicago, IL 60611 map it

Audience: Faculty/Staff - Student - Post Docs/Docs - Graduate Students

Contact: Peter Penzes   (312) 503-5379

Group: Center for Autism and Neurodevelopment

Category: Lectures & Meetings

Description:

Ted Abel, PhD
Director, Iowa Neuroscience Institute 
Chair and Departmental Executive Officer, Department of Neuroscience & Pharmacology
University of Iowa Carver College of Medicine

Abstract:

It is consistently reported that changes in striatal structure and function occur in neurodevelopmental disorder (NDD) patients, suggesting a close connection between the striatum and NDD pathophysiology. Microdeletion of one copy of the 16p11.2 chromosomal region represents a common genetic risk variant for NDDs. Therefore, we interrogated the role of striatal networks in NDDs using the 16p11.2 deletion mouse model. We previously found that 16p11.2 deletion mice exhibit impairments in striatum-dependent behaviors, including hyperactive behavior and male-specific impairments in reward learning. We have now investigated the role of medium spiny neurons (MSN), the major neuronal population of the striatum, in behavioral alterations of the 16p11.2 mouse. We examined transcriptomic changes in 16p11.2 mice in a cell-type specific manner by performing single nuclei RNA-sequencing (snRNA-seq) on striatal neurons. In males, the D1-MSNs and D2-MSNs displayed 103 and 160 significant differentially expressed genes (DEGs), respectively. However, in females the D1-MSNs and D2-MSNs showed 25 and 27 significant DEGs, respectively, suggesting a differential impact of the 16p11.2 deletion on striatal pathways by sex. To determine the role of D1-MSNs and D2-MSNs in behavioral alterations of 16p11.2 mice, we used an intersectional approach. Crossing a 16p11.2 floxed mouse (16p11.2flx) to a cell type-specific Cre recombinase mouse line allowed us to investigate the distinct role of 16p11.2 deletion in D1-MSNs and D2-MSNs. sD1-CRE x 16p11.2flx mice showed that 16p11.2 deletion in D1-MSNs mediated reward learning deficits in male mice, and A2A-CRE x 16p11.2flx mice revealed that 16p11.2 deletion in D2-MSNs mediated hyperactive behavior in male mice. These results suggest distinct contributions of D1-MSNs and D2-MSNs in behavioral alterations relevant to NDDs, consistent with our snRNAseq results. Circuit-specific study of the 16p11.2 deletion model will help uncover the mechanisms that underlie core NDD symptoms, thereby laying the groundwork for future therapeutic development.  

 

 

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