Role of autism risk genes in prefrontal circuits underlying social processing in mice

  • Awarded: 2019
  • Award Type: Pilot
  • Award #: 610850

Social processing has been established as one of the six trans-diagnostic core domains (according to the Research Domain Criteria framework) of neuropsychiatric disorders, including autism spectrum disorders (ASD), yet very little is known about the link between mutations in ASD risk genes and neural circuits underlying social processing.

The prefrontal cortex (PFC) has been shown to play an essential role in both implicit and explicit social processing in humans and in animal models (reviewed in 1). Recent genetic and transcriptomic studies have shown that many ASD risk genes are enriched in fetal and infant PFC layer (L) 5/6 projection neurons. Further, mechanistic studies in animals have demonstrated that subcortically projecting L5/6 neurons in the medial PFC (mPFC) are disrupted in several ASD mouse models.

Hirofumi Morishita now proposes to study mouse models harboring mutations in various ASD risk genes to identify converging circuit deficits within the mPFC and to establish preclinical strategies for ameliorating social interaction deficits caused by these altered circuits. He and his team will first identify specific mPFC L5/6 neurons projecting to selective subcortical targets that are vulnerable to multiple different ASD risk gene manipulations and that are responsible for social behaviors. He will then utilize strategies to manipulate these neurons that ameliorate social behavior deficits.

In a preliminary study, Morishita identified the limbic thalamus as the most prominent projection target of the mPFC that is preferentially recruited by social interaction. He hypothesizes that multiple different ASD risk genes cause disruptions to this mPFC L5/6 projection neurons to limbic thalamus pathway, thereby contributing to social behavior deficits. He plans to directly measure (using fiber photometry) and manipulate (via optogenetics) the neural activity of this mPFC L5/6 to limbic thalamus pathway during naturalistic free moving social behaviors in male and female mice  in which various ASD risk genes (Fmr1, Cntnap2, Pten, Tsc2) have been deleted. Identification of specific PFC circuits that modulate social behavior and whose functions are affected by mutations in ASD risk genes will point toward potential targets that allow amelioration of social processing deficits in ASD.


1.Bicks L.K. et al. Front. Psychol. 6, 1805 (2015) PubMed
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