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

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.

[1]  Karl J. Friston,et al.  MRI analysis of an inherited speech and language disorder: structural brain abnormalities. , 2002, Brain : a journal of neurology.

[2]  Karl J. Friston,et al.  Neural basis of an inherited speech and language disorder. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Christopher A Walsh,et al.  Characterization of Foxp2 and Foxp1 mRNA and protein in the developing and mature brain , 2003, The Journal of comparative neurology.

[4]  H. Yin,et al.  The role of the basal ganglia in habit formation , 2006, Nature Reviews Neuroscience.

[5]  F. Vargha-Khadem,et al.  Behavioural analysis of an inherited speech and language disorder: comparison with acquired aphasia. , 2002, Brain : a journal of neurology.

[6]  T. Clark,et al.  Estimating the number of coding mutations in genotypic and phenotypic driven N-ethyl-N-nitrosourea (ENU) screens: revisited , 2006, Mammalian Genome.

[7]  C. Scharff,et al.  FoxP2 Expression in Avian Vocal Learners and Non-Learners , 2004, The Journal of Neuroscience.

[8]  M. Mishkin,et al.  Language fMRI abnormalities associated with FOXP2 gene mutation , 2003, Nature Neuroscience.

[9]  Rui M. Costa,et al.  Rapid Alterations in Corticostriatal Ensemble Coordination during Acute Dopamine-Dependent Motor Dysfunction , 2006, Neuron.

[10]  D. Geschwind,et al.  Identification of the transcriptional targets of FOXP2, a gene linked to speech and language, in developing human brain. , 2007, American journal of human genetics.

[11]  C. A. French,et al.  Generation of mice with a conditional Foxp2 null allele , 2007, Genesis.

[12]  Simon E. Fisher,et al.  Localisation of a gene implicated in a severe speech and language disorder , 1997, Nature Genetics.

[13]  K. Kaestner,et al.  Unified nomenclature for the winged helix/forkhead transcription factors. , 2000, Genes & development.

[14]  M. Mishkin,et al.  FOXP2 and the neuroanatomy of speech and language , 2005, Nature Reviews Neuroscience.

[15]  P. Lieberman.  On the nature and evolution of the neural bases of human language. , 2002, American journal of physical anthropology.

[16]  D. Geschwind,et al.  High-throughput analysis of promoter occupancy reveals direct neural targets of FOXP2, a gene mutated in speech and language disorders. , 2007, American journal of human genetics.

[17]  Johannes Schwarz,et al.  A Humanized Version of Foxp2 Affects Cortico-Basal Ganglia Circuits in Mice , 2009, Cell.

[18]  D. Bishop,et al.  Genetic and environmental risks for specific language impairment in children. , 2001, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[19]  A. Monaco,et al.  A forkhead-domain gene is mutated in a severe speech and language disorder , 2001, Nature.

[20]  K. Davies,et al.  Functional genetic analysis of mutations implicated in a human speech and language disorder. , 2006, Human molecular genetics.

[21]  Sarah E. London,et al.  Parallel FoxP1 and FoxP2 Expression in Songbird and Human Brain Predicts Functional Interaction , 2004, The Journal of Neuroscience.

[22]  D. Lovinger,et al.  Dynamic reorganization of striatal circuits during the acquisition and consolidation of a skill , 2009, Nature Neuroscience.

[23]  C. Scharff,et al.  Incomplete and Inaccurate Vocal Imitation after Knockdown of FoxP2 in Songbird Basal Ganglia Nucleus Area X , 2007, PLoS biology.

[24]  A. Monaco,et al.  Deciphering the genetic basis of speech and language disorders. , 2003, Annual review of neuroscience.

[25]  J. Tomblin,et al.  Prevalence of specific language impairment in kindergarten children. , 1997, Journal of speech, language, and hearing research : JSLHR.

[26]  Anatol C. Kreitzer,et al.  Striatal Plasticity and Basal Ganglia Circuit Function , 2008, Neuron.

[27]  N. Sykes,et al.  Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits. , 2005, American journal of human genetics.

[28]  Xin Jin,et al.  Frontiers in Integrative Neuroscience Integrative Neuroscience , 2022 .

[29]  A. Monaco,et al.  FOXP2 expression during brain development coincides with adult sites of pathology in a severe speech and language disorder. , 2003, Brain : a journal of neurology.

[30]  Steve D. M. Brown,et al.  A gene-driven approach to the identification of ENU mutants in the mouse , 2002, Nature Genetics.

[31]  M. Nicolelis,et al.  Differential Corticostriatal Plasticity during Fast and Slow Motor Skill Learning in Mice , 2004, Current Biology.

[32]  Constance Scharff,et al.  FOXP2 as a molecular window into speech and language. , 2009, Trends in genetics : TIG.

[33]  Kaoru Takahashi,et al.  Expression of Foxp2, a gene involved in speech and language, in the developing and adult striatum , 2003, Journal of neuroscience research.

[34]  E. Jarvis,et al.  Learned Birdsong and the Neurobiology of Human Language , 2004, Annals of the New York Academy of Sciences.

[35]  Steve D. M. Brown,et al.  Impaired Synaptic Plasticity and Motor Learning in Mice with a Point Mutation Implicated in Human Speech Deficits , 2008, Current Biology.

[36]  Shanru Li,et al.  Transcriptional and DNA Binding Activity of the Foxp1/2/4 Family Is Modulated by Heterotypic and Homotypic Protein Interactions , 2004, Molecular and Cellular Biology.