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

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Van Rhijn,  Jon Ruben
Neurogenetics of Vocal Communication Group, MPI for Psycholinguistics, Max Planck Society;
Donders Institute for Brain, Cognition and Behaviour, External Organizations;
Language and Genetics Department, MPI for Psycholinguistics, Max Planck Society;
International Max Planck Research School for Language Sciences, MPI for Psycholinguistics, Max Planck Society;

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Fisher,  Simon E.
Donders Institute for Brain, Cognition and Behaviour, External Organizations;
Language and Genetics Department, MPI for Psycholinguistics, Max Planck Society;

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Vernes,  Sonja C.
Neurogenetics of Vocal Communication Group, MPI for Psycholinguistics, Max Planck Society;
Donders Institute for Brain, Cognition and Behaviour, External Organizations;

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Citation

Van Rhijn, J. R., Fisher, S. E., Vernes, S. C., & Nadif Kasri, N. (2018). Foxp2 loss of function increases striatal direct pathway inhibition via increased GABA release. Brain Structure and Function, 223(9), 4211-4226. doi:10.1007/s00429-018-1746-6.


Cite as: http://hdl.handle.net/21.11116/0000-0002-0BC1-8
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.