Understanding the basic neurobiology of Pitt-Hopkins syndrome

  • Awarded: 2012
  • Award Type: Explorer
  • Award #: 253337

J. David Sweatt and his colleagues at the University of Alabama at Birmingham carried out a set of mechanistic studies, using laboratory animals and cellular model systems, to understand the role of the TCF4 transcription factor in cognitive and central nervous system function. As a transcription factor, TCF4 directly regulates gene expression in the brain during development and in adulthood.

The cognitive dysfunction associated with the loss of one copy of the TCF4 gene, termed haplo-insufficiency, in humans leads to Pitt-Hopkins syndrome, an autism-related disorder associated with pronounced learning deficits. Pitt-Hopkins syndrome is extremely debilitating, making this a priority area for both neurobiological studies and drug development.

Understanding the role of gene transcriptional regulation in cognitive function is a long-standing focus of Sweatt’s laboratory. In their effort to understand cognitive dysfunction in Pitt-Hopkins syndrome, the researchers undertook investigations of the neurobiological function of TCF4. They hoped to gain insights into the role of transcriptional regulation in autism spectrum disorders more generally.

Over the past year, Sweatt and his colleagues have generated preliminary results that support the validity of using the TCF4 haplo-insufficiency mouse line both as a model for studying Pitt-Hopkins-related cognitive function and as a potential drug-screening platform.

Their findings suggest that TCF4 regulates the brain’s ability to store memories by actively regulating transcription during learning and memory formation. In addition, disruption of these processes underlies the pronounced learning, memory, social interaction and language dysfunction seen in Pitt-Hopkins syndrome.

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