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FOXP1 negatively regulates intrinsic excitability in D2 striatal projection neurons by promoting inwardly rectifying and leak potassium currents

Molecular Psychiatry volume 26, pages 1761–1774 (2021)Cite this article

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Abstract

Heterozygous loss-of-function mutations in the transcription factor FOXP1 are strongly associated with autism. Dopamine receptor 2 expressing (D2) striatal projection neurons (SPNs) in heterozygous Foxp1 (Foxp1+/−) mice have higher intrinsic excitability. To understand the mechanisms underlying this alteration, we examined SPNs with cell-type specific homozygous Foxp1 deletion to study cell-autonomous regulation by Foxp1. As in Foxp1+/− mice, D2 SPNs had increased intrinsic excitability with homozygous Foxp1 deletion. This effect involved postnatal mechanisms. The hyperexcitability was mainly due to down-regulation of two classes of potassium currents: inwardly rectifying (KIR) and leak (KLeak). Single-cell RNA sequencing data from D2 SPNs with Foxp1 deletion indicated the down-regulation of transcripts of candidate ion channels that may underlie these currents: Kcnj2 and Kcnj4 for KIR and Kcnk2 for KLeak. This Foxp1-dependent regulation was neuron-type specific since these same currents and transcripts were either unchanged, or very little changed, in D1 SPNs with cell-specific Foxp1 deletion. Our data are consistent with a model where FOXP1 negatively regulates the excitability of D2 SPNs through KIR and KLeak by transcriptionally activating their corresponding transcripts. This, in turn, provides a novel example of how a transcription factor may regulate multiple genes to impact neuronal electrophysiological function that depends on the integration of multiple current types – and do this in a cell-specific fashion. Our findings provide initial clues to altered neuronal function and possible therapeutic strategies not only for FOXP1-associated autism but also for other autism forms associated with transcription factor dysfunction.

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Fig. 1: Cell-autonomous Foxp1 deletion leads to increased intrinsic excitability in D2 SPNs but does not affect their morphology.
Fig. 2: Cs+-sensitive inwardly rectifying K+ current (KIR) is downregulated in D2 SPNs with embryonic Foxp1 deletion.
Fig. 3: Cs+-insensitive KLeak is preferentially downregulated by Foxp1 deletion.
Fig. 4: Cell-autonomous, embryonic deletion of Foxp1 increases the intrinsic excitability in D1 SPNs, but subthreshold properties are unchanged.
Fig. 5: Gene expression changes assayed with single-cell RNA-seq implicate specific KIR and KLeak subtypes being downregulated with Foxp1 deletion.

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Acknowledgements

Special thanks to Mathew Harper for technical help. Funding provided by the Simons Foundation (SFARI 573689 and 401220) and NIH (MH102603) to GK and JG.

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  1. These authors contributed equally: Sheridan Cavalier, Volodymyr Rybalchenko

Authors and Affiliations

  1. Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

    Nitin Khandelwal, Sheridan Cavalier, Volodymyr Rybalchenko, Ashwinikumar Kulkarni, Ashley G. Anderson, Genevieve Konopka & Jay R. Gibson

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NK, designed and performed experiments, analyzed data, wrote manuscript; SC, performed experiments, analyzed data; VR, designed and performed experiments, analyzed data; AK, analyzed data, created figures; AGA, analyzed data; GK, designed experiments, wrote manuscript; JRG, designed experiments, wrote manuscript.

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Correspondence to Genevieve Konopka or Jay R. Gibson.

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Khandelwal, N., Cavalier, S., Rybalchenko, V. et al. FOXP1 negatively regulates intrinsic excitability in D2 striatal projection neurons by promoting inwardly rectifying and leak potassium currents. Mol Psychiatry 26, 1761–1774 (2021). https://doi.org/10.1038/s41380-020-00995-x

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