Foxp2 loss of function increases striatal direct pathway inhibition via increased GABA release

Jon-Ruben van Rhijn, Simon E Fisher, Sonja C Vernes, Nael Nadif Kasri

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

Heterozygous mutations of the Forkhead-box protein 2 (FOXP2) gene in humans cause childhood apraxia of speech. Loss of Foxp2 in mice is known to affect striatal development and impair motor skills. However, it is unknown if striatal excitatory/inhibitory balance is affected during development and if the imbalance persists into adulthood. We investigated the effect of reduced Foxp2 expression, via a loss-of-function mutation, on striatal medium spiny neurons (MSNs). Our data show that heterozygous loss of Foxp2 decreases excitatory (AMPA receptor-mediated) and increases inhibitory (GABA receptor-mediated) currents in D1 dopamine receptor positive MSNs of juvenile and adult mice. Furthermore, reduced Foxp2 expression increases GAD67 expression, leading to both increased presynaptic content and release of GABA. Finally, pharmacological blockade of inhibitory activity in vivo partially rescues motor skill learning deficits in heterozygous Foxp2 mice. Our results suggest a novel role for Foxp2 in the regulation of striatal direct pathway activity through managing inhibitory drive.

Original languageEnglish
Pages (from-to)4211-4226
Number of pages16
JournalBrain Structure and Function
Volume223
Issue number9
Early online date5 Sept 2018
DOIs
Publication statusPublished - Dec 2018

Keywords

  • Animals
  • Corpus striatum/physiology
  • Excitatory postsynaptic potentials
  • Forkhead transcription factors/genetics
  • Glutamate decarboxylase/metabolism
  • Inhibitory postsynaptic potentials
  • Learning/physiology
  • Mice, inbred C57BL
  • Mice, transgenic
  • Motor skills
  • Neurons/physiology
  • Receptors, dopamine D1/physiology
  • Repressor proteins/genetics
  • Synapses/physiology
  • gamma-Aminobutyric acid/physiology

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