FOXP1 orchestration of neuronal function in the striatum

  • Awarded: 2016
  • Award Type: Pilot
  • Award #: 401220

The gene encoding the transcription factor FOXP1 is strongly implicated in the etiology of individuals with autism spectrum disorder (ASD) and of those with intellectual disability. FOXP1 is among the 40 highest-ranked candidate ASD risk genes (according to SFARI Gene). Brain-wide deletion of FOXP1 in mice results in altered behaviors relevant to ASD1.

Recent work has identified specific cell types likely to be disrupted across the diverse etiologies of ASD. These include two types of striatal medium spiny neurons (MSNs) — one that expresses dopamine receptor 1a (D1) and another that expresses dopamine receptor 2 (D2). FOXP1 is highly expressed in these neurons.

Jay Gibson and Genevieve Konopka hypothesize that FOXP1 regulates cell-specific signaling pathways within D1 and D2 MSNs that are critical for behaviors affected in ASD. Gibson and Konopka recently began examining functional alterations associated with FOXP1 heterozygosity (FOXP1+/-), the most common form of FOXP1-associated ASD1. They showed that FOXP1 is important for gene expression and neuronal function in the striatum as well as striatal-dependent behaviors. Most notably, they observed that D2 MSNs, but not D1 MSNs, are hyperexcitable in these mice. How loss of FOXP1 function induces hyperexcitability in just D2 MSNs remains unclear.

Gibson and Konopka propose to address the mechanism underlying this cell-type specificity by employing experimental strategies that are cell-type specific, thereby avoiding indirect circuit effects. Ultimately, the results of this work will help to clarify how alterations in FOXP1 lead to ASD, and will aid in our more general understanding of how mutations that lead to neural circuit defects cause ASD-related behaviors.



1.Araujo D.J. et al. Genes Dev. 29, 2081-2096 (2015) PubMed
Subscribe to our newsletter and receive SFARI funding announcements and news