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. 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. The FOXP2 transcription factor is highly similar in many vertebrate species, with conserved expression in neural circuits related to sensorimotor integration and motor learning. 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.
Groszer
Matthias
M
Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, United Kingdom.
Keays
David A
DA
Deacon
Robert M J
RM
de Bono
Joseph P
JP
Prasad-Mulcare
Shweta
S
Gaub
Simone
S
Baum
Muriel G
MG
French
Catherine A
CA
Nicod
Jérôme
J
Coventry
Julie A
JA
Enard
Wolfgang
W
Fray
Martin
M
Brown
Steve D M
SD
Nolan
Patrick M
PM
Pääbo
Svante
S
Channon
Keith M
KM
Costa
Rui M
RM
Eilers
Jens
J
Ehret
Günter
G
Rawlins
J Nicholas P
JN
Fisher
Simon E
SE
D000483:Alleles; D000818:Animals; D051858:Forkhead Transcription Factors / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007858:Learning / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009048:Motor Skills / Q000502:physiology*; D009473:Neuronal Plasticity / Q000235:genetics*; D017354:Point Mutation; D012097:Repressor Proteins / Q000235:genetics*; D013064:Speech Disorders / Q000235:genetics*; D014828:Vocalization, Animal / Q000502:physiology
D051858:Forkhead Transcription Factors; C432918:Foxp2 protein, mouse; D012097:Repressor Proteins