Role of PTCHD1 in thalamic reticular nucleus function and autism

  • Awarded: 2014
  • Award Type: Research
  • Award #: 307913

Genetics is important in the etiology of autism, with many identified candidate genes linking autism to synaptic pathology. Although understanding autism at the level of genes and synapses is essential, developing novel therapeutics requires an understanding of the dysfunction of neural circuits that control autism-related behavior. This entails knowledge of the affected neuronal subtypes and how their interactions may be disrupted in distinct brain regions and developmental stages.

PTCHD1 is a recently identified autism risk gene that is mutated or deleted in about 1 percent of all autism cases. Guoping Feng and his colleagues at the Massachusetts Institute of Technology found that this gene is selectively expressed in the thalamic reticular nucleus (TRN) during development, and continues to be enriched there throughout adult life. This brain structure controls the flow of information from the outside world to the brain’s cortex, where higher-level perception, thinking and planning take place.

Michael Halassa and his group at New York University have unique experience studying how this structure mediates normal brain function, including studying the switch between processing outside stimuli and engaging in internal cognitive tasks. Halassa and Feng are equipped to dissect disruption of the structure in autism, and to study whether TRN circuit deficit is a common mechanism explaining the sensory overload commonly attributed to autism.

In this collaborative study, the Feng and Halassa labs aim to use mice lacking PTCHD1 and a multilevel approach to understand the molecular nature of PTCHD1 gene mutations and their impact on firing properties of individual TRN neurons as well as on TRN-mediated cortical network activities. They also aim to understand how these defects are related to abnormal sensory processing and cognitive behavior in autism.

Because sensory and cognitive deficits are common across many forms of autism, TRN inhibitory dysfunction may be a unifying physiological alteration in autism. The researchers’ work may set the stage for novel therapies targeting TRN microcircuits.

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