Mutations in FOXP1 are among the most significant recurrent de novo mutations associated with autism spectrum disorder (ASD). Genevieve Konopka and Jay Gibson have begun to elucidate the cell autonomous role of Foxp1 in mouse striatum. Their findings, combining electrophysiological measurements and RNA-sequencing data, suggest that loss of Foxp1 in dopamine receptor 2 (D2) spiny projection neurons (SPNs) leads to hyperexcitability and alters gene expression changes critical for SPN molecular identity and function. This suggests that Foxp1 plays an important role in the identity and function of D2-expressing SPNs in the striatum. Subsequent experiments, funded in part by a SFARI Pilot Award, have shown that D2-expressing SPNs and markers of mature SPNs are significantly reduced in mice lacking Foxp1 specifically in D2-expressing SPNs¹. These changes in altered striatal cellular composition could be due to a combination of cell fate changes, changes in cell migration, cell death and/or excitotoxicity of D2-expressing SPNs with loss of Foxp1. Moreover, mice with loss of Foxp1 in D2-expressing SPNs have significant motor-learning deficits and are hyperactive¹, supporting the idea that alterations in striatal circuits could underlie relevant behaviors in individuals with FOXP1-mediated ASD.

Based on these data, Konopka and Gibson hypothesize that loss of Foxp1 in D2-expressing neurons alters transcriptional cascades that result in hyperexcitability of D2-expressing SPNs, ultimately leading to deficits in motor behaviors relevant to ASD. They will test this hypothesis with the following four specific aims: 1) determine the cell-autonomous transcriptional programs regulated by Foxp1 in early striatal development; 2) assess the role of Foxp1 on striatal cell fate, survival and migration; 3) determine the molecular mechanisms underlying the changes in neuronal excitability observed with loss of Foxp1; and 4) determine whether D1-expressing SPNs are resistant to loss of Foxp1 via compensation by Foxp2. The results from these investigations should aid in developing novel strategies for normalizing striatal physiology in the treatment of certain forms of ASD.

1. Anderson A.G. et al. bioRxiv (2019) Preprint