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

AbstractHeterozygous 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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Duration differences of corticostriatal responses in striatal projection neurons depend on calcium activated potassium currents

Frontiers in Systems Neuroscience ◽

10.3389/fnsys.2013.00063 ◽

2013 ◽

Vol 7 ◽

Cited By ~ 8

Author(s):

Mario A. Arias-García ◽

Dagoberto Tapia ◽

Edén Flores-Barrera ◽

Jesús E. Pérez-Ortega ◽

José Bargas ◽

...

Keyword(s):

Potassium Currents ◽

Projection Neurons ◽

Striatal Projection Neurons

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Cell-type-specific regulation of neuronal intrinsic excitability by macroautophagy

eLife ◽

10.7554/elife.50843 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 8

Author(s):

Ori J Lieberman ◽

Micah D Frier ◽

Avery F McGuirt ◽

Christopher J Griffey ◽

Elizabeth Rafikian ◽

...

Keyword(s):

Potassium Channel ◽

Dendritic Structure ◽

Intrinsic Excitability ◽

Projection Neurons ◽

Inwardly Rectifying Potassium Channel ◽

Cell Type Specific ◽

Subcortical Nuclei ◽

Specific Regulation ◽

Inwardly Rectifying

The basal ganglia are a group of subcortical nuclei that contribute to action selection and reinforcement learning. The principal neurons of the striatum, spiny projection neurons of the direct (dSPN) and indirect (iSPN) pathways, maintain low intrinsic excitability, requiring convergent excitatory inputs to fire. Here, we examined the role of autophagy in mouse SPN physiology and animal behavior by generating conditional knockouts of Atg7 in either dSPNs or iSPNs. Loss of autophagy in either SPN population led to changes in motor learning but distinct effects on cellular physiology. dSPNs, but not iSPNs, required autophagy for normal dendritic structure and synaptic input. In contrast, iSPNs, but not dSPNs, were intrinsically hyperexcitable due to reduced function of the inwardly rectifying potassium channel, Kir2. These findings define a novel mechanism by which autophagy regulates neuronal activity: control of intrinsic excitability via the regulation of potassium channel function.

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