Researchers Uncover Genetic Changes Associated with Autism and Schizophrenia

Copy number variants (CNVs) are genetic changes where segments of chromosomes differ from the usual number of copies. These variations have gained increasing recognition for their role in brain structure and their link to psychiatric disorders. Although CNVs often affect multiple genes, the specific contributions of individual genes within these variants to brain development and psychiatric conditions remain largely unexplored.

One prominent example is the 22q11.2 region on human chromosome 22, which contains over 30 protein-coding genes. Among these, the Tbx1 gene stands out as a critical regulator of stem cell function in the brain, as shown in earlier studies by Hiroi and colleagues. Variants in Tbx1 are strongly associated with a range of neurodevelopmental and psychiatric disorders, including autism spectrum disorders, schizophrenia, intellectual disability, and developmental delay. Gaining a better understanding of Tbx1 and other genes in this region is crucial to uncovering the mechanisms that drive CNV-related brain abnormalities and psychiatric outcomes.

“Dr. Hiroi’s groundbreaking research in the Department of Pharmacology has greatly advanced our understanding of the genetic foundations of psychiatric disorders, such as autism spectrum disorder and schizophrenia,” said Daniel Lodge, PhD, professor and chair of the Department of Pharmacology at the Long School of Medicine at UT Health San Antonio. “His recent study on Tbx1 not only highlights the complexity of gene-phenotype interactions but also demonstrates how precise volumetric analyses can reveal the neural correlates of behavioral impairments, offering a path toward potential therapeutic interventions.”

Brain volume differences

In this study, the research team created mice lacking the Tbx1 gene and used volumetric MRI analysis to compare their brain volumes with wild-type mice. They also assessed social behavior differences between the two groups of mice.

Hiroi found that Tbx1-deficient mice had a reduced volume in their amygdala and surrounding cortical areas, particularly in the amygdalo-piriform transition area, a small and poorly understood subregion of the amygdala. This region is connected to several brain areas involved in processing sensory and emotional cues, and the amygdala itself is vital for regulating emotional behavior.

Social interaction preference affected

Mice, like humans, learn to use cues and context to assess the social value of experiences, Hiroi explained. In this study, when given a choice between two enclosures—one with another mouse and one without—wild-type mice consistently chose the enclosure with the other mouse. In contrast, Tbx1-deficient mice showed no strong preference for the presence of another mouse, instead selecting a location based on other factors, such as preferred bedding type.

“This suggests that Tbx1 deficiency may impact the ability to evaluate the positive value of social experiences,” Hiroi said.

What’s next?

Hiroi is expanding the research by collaborating with Jason Pugh, PhD, in the UT Health San Antonio Department of Cellular and Integrative Physiology. Together, they will examine the excitability of specific neurons in the amygdalo-piriform transition area of Tbx1-deficient mice. They are also developing models to restore Tbx1 heterozygosity (having two versions of the same gene) at any stage of development. Once completed, Hiroi plans to use this model to identify the critical developmental period for amygdala shrinkage.

Hiroi noted that the reduction in amygdala volume likely begins during the embryonic phase, suggesting that therapeutic intervention could target this period. Additionally, the degree of amygdala shrinkage might serve as a biomarker for the impaired appreciation of social experiences in individuals with autism spectrum disorder or schizophrenia.

“This study could serve as a catalyst to connect basic science with human brain imaging studies and research on neurodevelopmental disorders, areas in which UT Health San Antonio already excels,” Hiroi added.

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