# Regulation of 22q11 Genes in Embryonic and Adult Forebrain

> **NIH NIH R01** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2024 · $661,158

## Abstract

ABSTRACT
Layer 2/3 projection neurons (PNs) are critical nodes in association cortico-cortical (Ac-c) circuits, and likely
targets of neurodevelopmental disorder (NDD) pathology. In mouse models of 22q11.2 Deletion Syndrome
(22q11DS), which in humans confers risk for multiple clinically defined NDDs, Ac-c circuits are under-
connected, in part due to diminished layer 2/3 PN growth accompanied by mitochondrial oxidative stress. We
will use mouse 22q11DS genetic models to test the hypothesis that Ac-c circuit pathology in NDD reflects
selective, mitochondria-dependent developmental dysregulation of layer 2/3 PN long-range
connections, leading to disordered synaptic organization, disconnection, and dysfunction. We combine
genetic, physiological, transcriptomic, proteomic, and behavioral approaches to assess how 22q11 deletion
alters identity and function of layer 2/3 PNs to result in individually variable behavior and circuit pathology. In
Specific Aim 1 we determine whether excitatory (E) vs. inhibitory (I) synaptic sites on layer 2/3 PNs that make
long-range connections are altered by NDD pathogenesis, including that due to 22q11 deletion, leading to Ac-c
circuit disconnection and dysfunction. Our data will provide foundational insight into cellular, physiological and
transcriptional identities of typical layer 2/3 Ac-c vs. 5/6 PNs, as well as consequences of NDD pathology for
E/I balance in circuits defined by long-range Ac-c connections. In Specific Aim 2, we assess mitochondrial
function in developing layer 2/3 PNs as they generate pre- and post-synaptic domains to define mature
microcircuits. We analyze how NDD pathogenesis due to 22q11 deletion disrupts developing and mature
mitochondrial regulation of Ac-c connectivity. Our data will provide fundamental characterization of
mitochondria deployment, bioenergetics, and proteomic identities in typical developing and mature layer 2/3 vs.
5/6 PNs, including mitochondria at layer 2/3 PN synapses. In parallel, we will define how mitochondrial identity
and function is compromised by 22q11 deletion. In Specific Aim 3, we analyze how mitochondrial antioxidant
defense influences behaviors that rely upon long range Ac-c connections made by layer 2/3 PNs. We assess
individual variability in cognitive, mnemonic, sensory gating and social behaviors. Our data will resolve whether
a specific dimension of mitochondrial function—clearance of reactive oxygen species generated by oxidative
phosphorylation—varies individually to disrupt Ac-c circuit dependent behaviors and circuits. Data collected
from these Specific Aims will provide a framework for understanding optimal mitochondrial regulation of Ac-c
circuit development and function and its disruption in NDDs. We will resolve contributions of mitochondrial
function and antioxidant defense to 22q11 deletion-mediated Ac-c disconnection and related behavioral
deficits. Our work will define whether emerging therapies, including antioxidants and other metabolic
int...

## Key facts

- **NIH application ID:** 10906241
- **Project number:** 5R01HD042182-20
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** ANTHONY S LAMANTIA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $661,158
- **Award type:** 5
- **Project period:** 2003-04-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10906241

## Citation

> US National Institutes of Health, RePORTER application 10906241, Regulation of 22q11 Genes in Embryonic and Adult Forebrain (5R01HD042182-20). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10906241. Licensed CC0.

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