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Selective deletion of Foxp2 in motor-skill learning circuits


Fisher,  Simon E.
Language and Genetics Department, MPI for Psycholinguistics, Max Planck Society;

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French, C., Feliciano, C., Jin, X., Fisher, S. E., & Costa, R. (2012). Selective deletion of Foxp2 in motor-skill learning circuits. Poster presented at the 42nd annual meeting of the Society for Neuroscience [Neuroscience 2012] Poster# 57.09/J9, New Orleans, LA.

Mutations in the FOXP2 gene cause a severe neurodevelopmental speech and language disorder. In the KE family, a heterozygous FOXP2 mutation is inherited in a dominant fashion. Affected individuals have difficulty mastering the sequences of orofacial motor movements necessary for fluent speech, a feature which is proposed to be a core deficit. A number of recent reports have also described more generalised deficits in fine-motor control inother patients with FOXP2 disruptions. FOXP2 encodes a transcription factor which is highly conserved in many vertebrate species and is expressed in cortico-striatal and cortico-cerebellar circuits which are required for sensorimotor integration and motor-skill learning. Mice carrying the KE-family mutation (Foxp2-R552H/+) have motor-skill learning deficits and lack striatal long-term depression. We recently recorded striatal activity in these animals in vivo during training on the accelerating rotarod. Mutants showed an abnormally high ongoing firing rate which was negatively modulated during skill acquisition, contrasting with the positive modulation seen in wild-type animals. We are now using an operant task to investigate the learning and performance of rapid motor sequences in mice with selective deletion of Foxp2 in the cortex, striatum or cerebellar Purkinje cells. Mice must press a lever 8 times to receive a food reward. After 12 days a time constraint is added, and the sequence of 8 presses must be completed at increasingly high speeds. We are examining the microstructure of behaviour during this task to dissect the nature of motor-skill learning deficits in each of the Foxp2 mutants. Surprisingly, Foxp2-R552H/+ and Foxp2-S321X/+ mice (the S321X allele is effectively a null) produced sequences of a shorter duration compared to wild-types. This was likely due to a higher press rate. The time interval between sequences of presses was also reduced. Conversely, mice with cerebellar-specific Foxp2 deletion produced sequences of a longer duration, had a lower press rate and longer intervals between sequences. Similar, but less pronounced, changes were observed in mice with striatal-specific Foxp2 deletion. No changes were evident in mice with cortical-specific Foxp2 deletion.