Impaired Synaptic Plasticity and Motor Learning in Mice with a Point Mutation Implicated in Human Speech Deficits

The most well-described example of an inherited speech and language disorder is that observed in the multigenerational KE family, caused by a heterozygous missense mutation in the FOXP2 gene 1Lai C.S. Fisher S.E. Hurst J.A. Vargha-Khadem F. Monaco A.P. A forkhead-domain gene is mutated in a severe speech and language disorder.Nature. 2001; 413: 519-523Crossref PubMed Scopus (1430) Google Scholar. Affected individuals are characterized by deficits in the learning and production of complex orofacial motor sequences underlying fluent speech and display impaired linguistic processing for both spoken and written language 2Watkins K.E. Dronkers N.F. Vargha-Khadem F. Behavioural analysis of an inherited speech and language disorder: comparison with acquired aphasia.Brain. 2002; 125: 452-464Crossref PubMed Scopus (270) Google Scholar. The FOXP2 transcription factor is highly similar in many vertebrate species, with conserved expression in neural circuits related to sensorimotor integration and motor learning 3Fisher S.E. Marcus G.F. The eloquent ape: genes, brains and the evolution of language.Nat. Rev. Genet. 2006; 7: 9-20Crossref PubMed Scopus (157) Google Scholar, 4Vargha-Khadem F. Gadian D.G. Copp A. Mishkin M. FOXP2 and the neuroanatomy of speech and language.Nat. Rev. Neurosci. 2005; 6: 131-138Crossref PubMed Scopus (331) Google Scholar. In this study, we generated mice carrying an identical point mutation to that of the KE family, yielding the equivalent arginine-to-histidine substitution in the Foxp2 DNA-binding domain. Homozygous R552H mice show severe reductions in cerebellar growth and postnatal weight gain but are able to produce complex innate ultrasonic vocalizations. Heterozygous R552H mice are overtly normal in brain structure and development. Crucially, although their baseline motor abilities appear to be identical to wild-type littermates, R552H heterozygotes display significant deficits in species-typical motor-skill learning, accompanied by abnormal synaptic plasticity in striatal and cerebellar neural circuits.