# Identifying a critical developmental period for cognitive speed in a mouse model for neurodevelopmental disorders

> **NIH NIH F30** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2024 · $41,511

## Abstract

ABSTRACT
Cognitive impairments, which characterize many neurodevelopmental disorders, such as autism spectrum
disorder, schizophrenia, and intellectual disability, likely arise from aberrant neurodevelopmental processes.
Copy number variations (CNVs), such as the 22q11.2 hemizygous deletion, confer a very high risk for specific
cognitive deficits. We demonstrated that in mice, constitutive heterozygosity of Tbx1, a transcription factor
gene within the 22q11.2 CNV, resulted in reduced mature oligodendrocytes and myelination, and decreased
levels of Ng2 mRNA, a gene required for the production of oligodendrocyte precursor cells. These mice
showed reduced speed in completing a task in attentional set-shifting and increased latency in spatial memory
acquisition. Strikingly, conditional initiation of Tbx1 heterozygosity in stem cells during the neonatal (P1–P5),
but not the peripubertal (P21–P25) period, reduced the speed to perform a cognitive task in mice in a way
similar to constitutive Tbx1 heterozygous mice. Our results suggest that TBX1 expression during the neonatal
developmental period is critical for the normal development of myelin and cognitive speed; however, the
mechanism of TBX1 action is unknown. It is not known whether TBX1 expression during the neonatal period is
essential for the proliferation of stem cells that give rise to oligodendrocyte precursor cells for myelination,
which affects cognitive speed. Here, I propose experiments to increase our understanding of post-embryonic
mechanisms underlying the cognitive deficits associated with TBX1 deficiency. We hypothesize that TBX1 is
essential for the development of cognitive speed through the regulation of neonatal stem cells that produce
oligodendrocytes and myelination. To test this hypothesis, we will use conditional Tbx1 heterozygous mouse
models to induce Tbx1 heterozygosity in stem cells during the neonatal or postnatal periods or in
oligodendrocyte precursor cells during the neonatal period. In these mice, we will measure cognitive speed in
spontaneous alternation and attentional set-shifting (Aim 1) and assess cellular phenotypes in neonatal stem
cells, oligodendrocytes and their precursor cells, and myelination (Aim 2). Moreover, we have identified
thousands of potential target genes of the TBX1 transcription factor by ChIP-seq, among which FoxG1 is the
only gene that is associated with stem cells, neurodevelopmental disorders, and cerebral dysmyelination.
Therefore, we will determine the role of TBX1 in FoxG1 regulation (Aim 3). There are no reliable diagnostic
markers or cures for neurodevelopmental disorders. The results from this research will significantly advance
our knowledge of the neurobiological mechanisms that lead to neurodevelopmental disorders, a prerequisite
for the development of treatments based on precision medicine. Moreover, the multidisciplinary and
translational aspects of the proposed training plan will provide rigorous training for the applicant to tra...

## Key facts

- **NIH application ID:** 10900314
- **Project number:** 1F30MH134482-01A1
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Anne Marie Wells
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $41,511
- **Award type:** 1
- **Project period:** 2024-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10900314

## Citation

> US National Institutes of Health, RePORTER application 10900314, Identifying a critical developmental period for cognitive speed in a mouse model for neurodevelopmental disorders (1F30MH134482-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10900314. Licensed CC0.

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