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bioRxiv · 10.1101/2023.10.23.563675

FOXP1 regulates the development of excitatory synaptic inputs onto striatal neurons and induces phenotypic reversal with reinstatement

Khandelwal, N.·Kulkarni, A.·Ahmed, N.·Harper, M.·Konopka, G.·Gibson, J. R.
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Abstract

Long-range glutamatergic inputs from the cortex and thalamus are critical for motor and cognitive processing in the striatum. Transcription factors that orchestrate the development of these inputs are largely unknown. We investigated the role of a transcription factor and high-risk autism-associated gene, FOXP1, in the development of glutamatergic inputs onto spiny projection neurons (SPNs) in the striatum. We find that FOXP1 robustly drives the strengthening and maturation of glutamatergic input onto dopamine receptor 2-expressing SPNs (D2 SPNs) but has a comparatively milder effect on D1 SPNs. This process is cell-autonomous and is likely mediated through postnatal FOXP1 function at the postsynapse. We identified postsynaptic FOXP1-regulated transcripts as potential candidates for mediating these effects. Postnatal reinstatement of FOXP1 rescues electrophysiological deficits, reverses gene expression alterations resulting from embryonic deletion, and mitigates behavioral phenotypes. These results provide support for a possible therapeutic approach for individuals with FOXP1 syndrome.

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Khandelwal, N., Kulkarni, A., Ahmed, N., Harper, M., Konopka, G., Gibson, J. R.. 2023-10-24. FOXP1 regulates the development of excitatory synaptic inputs onto striatal neurons and induces phenotypic reversal with reinstatement. https://doi.org/10.1101/2023.10.23.563675

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