An aetiological Foxp2 mutation causes aberrant striatal activity and alters plasticity during skill learning

Abstract

Mutations in the human FOXP2 gene cause impaired speech development and linguistic deficits, which have been best characterised in a large pedigree called the KE family. The encoded protein is highly conserved in many vertebrates and is expressed in homologous brain regions required for sensorimotor integration and motor-skill learning, in particular corticostriatal circuits. Independent studies in multiple species suggest that the striatum is a key site of FOXP2 action. Here, we used in vivo recordings in awake-behaving mice to investigate the effects of the KE-family mutation on the function of striatal circuits during motor-skill learning. We uncovered abnormally high ongoing striatal activity in mice carrying an identical mutation to that of the KE family. Furthermore, there were dramatic alterations in striatal plasticity during the acquisition of a motor skill, with most neurons in mutants showing negative modulation of firing rate, starkly contrasting with the predominantly positive modulation seen in control animals. We also observed striking changes in the temporal coordination of striatal firing during motor-skill learning in mutants. Our results indicate that FOXP2 is critical for the function of striatal circuits in vivo, which are important not only for speech but also for other striatal-dependent skills.

Figure 1

Foxp2-R552H/+ mice show impaired motor-skill learning. (a) Latency to fall of wild-type and Foxp2-R552H/+ mice during training on the accelerating rotarod. Mice received 10 trials a day for five consecutive days. (b) Rate of learning in wild-type and Foxp2-R552H/+ mice during training on the accelerating rotarod. Error bars represent s.e.m.

Figure 2

Foxp2-R552H/+ mice have abnormally high ongoing striatal activity and show negative modulation of firing rate during skill learning. (a) Example of a single-unit waveform (top left). Units were distinguished from each other and from noise using interspike interval histograms (top right) and two-dimensional cluster separation based on principal component analysis, where the circled yellow cluster represents the unit and the grey cluster noise (bottom right). The stability of a unit recording over the course of a session was assessed using three-dimensional cluster displays with a time axis (bottom left). (b) Average ongoing firing rate in wild-type and Foxp2-R552H/+ mice. (c) Average firing rate modulation during running compared with intertrial intervals, during the first and last trials of a session, in wild-type and Foxp2-R552H/+ mice. Error bars represent s.e.m.

Figure 3

A higher proportion of task-related neurons decrease firing rate during skill learning in Foxp2-R552H/+ mice. (a) Examples of neurons from wild-type (top) and Foxp2-R552H/+ (bottom) mice that increased (left) or decreased (right) firing rate (impulses per second) during running compared with intertrial intervals. Green triangles represent the start of a trial and red circles the end. (b) Percentage of task-related neurons that increased or decreased firing rate during running compared with intertrial intervals, during the first and last trials of a session, in wild-type (top panel) and Foxp2-R552H/+ (bottom panel) mice. Error bars represent s.e.m.

Figure 4

The temporal coordination of striatal activity is altered during skill learning in Foxp2-R552H/+ mice. (a) Spike-triggered average histograms showing a neuron that is entrained to the local field potential (LFP) during intertrial intervals (left) but loses entrainment during running periods (right). (b) Percentage of neurons that lost entrainment from (top panel) or gained entrained to (bottom panel) the LFP between intertrial interval and running during the first and last trials of a session. Error bars represent s.e.m.