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

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

doi:10.1007/s00429-018-1746-6

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.

Highlights

Balanced neuronal activity between cortex, striatum and thalamus is essential for the generation of voluntary movements (Shepherd 2013)
Upon investigation of expression in juvenile mice (PND1114) we found that Foxp2 is expressed in most striatal D1R-medium spiny neurons (MSNs), in contrast to only a small fraction of D2RMSN (Fig. 1a)
Foxp2 expressing MSNs are spread throughout the striatum, we chose to focus on cells in the dorsolateral striatum, because of its connection to the motor cortex (Hunnicutt et al 2016)

Summary

Introduction

Balanced neuronal activity between cortex, striatum and thalamus is essential for the generation of voluntary movements (Shepherd 2013). Imbalanced activity within the striatum is known to disrupt complex motor behaviors, such as the production of spoken language (Peach 2004; SquareStorer et al 1990). FOXP2, the first single gene linked to a speech and language disorder (Lai et al 2001), is important for the correct execution of complex motor behaviors used for speech. Individuals with mutations in the FOXP2 gene have problems executing coordinated sequences of orofacial movements, which impede their speech [diagnosed as developmental verbal dyspraxia or childhood apraxia of speech (CAS)], while their general cognitive functioning and other aspects of motor coordination are usually less severely affected (MacDermot et al 2005; Morgan et al 2017). FoxP2 codes for a transcription factor (Devanna et al 2014; Vernes et al 2006, 2007) and plays important roles during the early development of the central

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