Developmental origins of cortical circuit dysfunction in a 22q11 deletion mouse model

Cortical circuit development is tightly regulated by programs of progenitor proliferation, neurogenesis, and neuronal maturation. Disruptions in these processes contribute to the cortical circuit pathology observed in neurodevelopmental disorders such as schizophrenia and autism, intellectual disability. The 22q11.2 deletion syndrome (22q11DS) is a major genetic risk factor for psychiatric illness and provides an optimal genetic model disease to explore how gene dosage imbalance impacts cortical circuit development. Study 1 examined the developmental origin of upper layer 2/3 projection neuron (PNs) deficits in the LgDel mouse model of 22q11DS. Bulk and single cell RNA sequencing revealed transient, cell state dependent changes in intermediate basal progenitors at the peak of upper layer neurogenesis. These changes are characterized by reduced proliferation, increased neurogenic gene expression and altered DNA methylation. The divergent progenitor progression resulted in a selective decline and shift in identity of L2/3 PNs generated during this critical developmental window, while earlier and later population of progenitors as well progeny remained unaffected. Study 2 investigated how 22q11 deletion alters L2/3 PN growth and development. LgDel neurons displayed oxidative stress, mitochondrial dysfunction, and reduced neurite growth. Treatment with the antioxidant N-acetylcysteine (NAC) improved axonal and dendritic growth but did not restore expression of deleted or differentially expressed genes in LgDel PNs. Instead, NAC induced a distinct antioxidant response via Nrf2 signaling pathway. Together, these studies link early transcriptional dysregulation in cortical progenitors to later metabolic and functional deficits in projection neurons, highlighting oxidative stress as a modifiable driver of cortical circuit dysfunction in 22q11DS.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Translational Biology, Medicine and Health

Department dc:contributor.department

Graduate School

Grantor dc:publisher

Virginia Tech

Year dc:date.issued

2026

Author dc:creator

• Rukh, Shah

Chair dc:contributor.committeechair

• LaMantia, Anthony-Samuel

Committee members dc:contributor.committeemember

• Fox, Michael A.
• Johnstone, Scott Robert
• Anton, Eva
• Purcell, Ryan Herndon
• Yu, Jia-Ray

• Progenitors
• Neurogenesis
• Mitochondrial Function
• Oxidative Stress
• Projection neurons
• Differentiation

Statement dc:rights

• Creative Commons Attribution-NoDerivatives 4.0 International

Licence dc:rights.uri

• http://creativecommons.org/licenses/by-nd/4.0/

Language dc:language.iso

en

Dc Identifier Other

vt_gsexam:45295

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/140867