Abstract
Disruptions of the FOXP2 gene cause a speech and language disorder involving difficulties in sequencing orofacial movements. FOXP2 is expressed in cortico-striatal and cortico-cerebellar circuits important for fine motor skills, and affected individuals show abnormalities in these brain regions. We selectively disrupted Foxp2 in the cerebellar Purkinje cells, striatum or cortex of mice and assessed the effects on skilled motor behaviour using an operant lever-pressing task. Foxp2 loss in each region impacted behaviour differently, with striatal and Purkinje cell disruptions affecting the variability and the speed of lever-press sequences, respectively. Mice lacking Foxp2 in Purkinje cells showed a prominent phenotype involving slowed lever pressing as well as deficits in skilled locomotion. In vivo recordings from Purkinje cells uncovered an increased simple spike firing rate and decreased modulation of firing during limb movements. This was caused by increased intrinsic excitability rather than changes in excitatory or inhibitory inputs. Our findings show that Foxp2 can modulate different aspects of motor behaviour in distinct brain regions, and uncover an unknown role for Foxp2 in the modulation of Purkinje cell activity that severely impacts skilled movements.
Highlights
The discovery that disruptions of one copy of the FOXP2 gene cause a severe speech and language disorder has generated substantial interest in elucidating the neural functions of the encoded protein
Previous whole-cell recordings of Purkinje cells in C57BL/6J mice did not reveal any difference in the parallel fibre to Purkinje cell input between males and females [38]
Since Foxp2 global knockouts have been reported to have a disproportionally small cerebellum [21, 22], we examined the morphology of the cerebellum in more detail in Foxp2-PCKO mice and controls at the level of its input stage, its integrative stage, and its output stage
Summary
The discovery that disruptions of one copy of the FOXP2 gene cause a severe speech and language disorder has generated substantial interest in elucidating the neural functions of the encoded protein. The Brain Cognition and Brain Disease Institute, Shenzhen a large multigenerational family (the KE family), where a missense mutation was found to be responsible for deficits in many facets of speech and language [1,2,3]. Less severe deficits are evident in aspects of non-verbal cognition [3, 6]. A core phenotype of the disorder is developmental verbal dyspraxia ( known as childhood apraxia of speech), where imprecise and inconsistent neural control of sequences of orofacial movements impedes development of fluent speech
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