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

Groszer, Matthias; Keays, David A.; Deacon, Robert M. J.; Bono, Joseph de; Prasad-Mulcare, Shweta; Gaub, Simone; Baum, Muriel G.; French, Catherine A.; Nicod, Jérôme; Coventry, Julie A.; Enard, Wolfgang; Fray, Martin; Brown, Steve; Nolan, Patrick M.; Pääbo, Svante; Channon, Keith M.; Costa, Rui M.; Eilers, Jens; Ehret, Günter; Rawlins, J. N. P.; Fisher, Simon E.

doi:10.1016/j.cub.2008.01.060

Cited by 261 publications

(459 citation statements)

References 37 publications

(54 reference statements)

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“…We first evaluated motor skill learning, given that mice lacking one functional allele of murine Foxp2 are reported to exhibit learning deficits on an accelerating rotarod and a tilted running wheel (30,31). However, mice homozygous for humanized Foxp2 (Foxp2 hum/hum ) performed at levels equivalent to those of their WT (Foxp2 wt/wt ) controls when tested by these two tasks (n = 9-10 per genotype; Figs.…”

Section: Resultsmentioning

confidence: 99%

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Humanized Foxp2 accelerates learning by enhancing transitions from declarative to procedural performance

Schreiweis

Bornschein

Burguière

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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141

136

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The acquisition of language and speech is uniquely human, but how genetic changes might have adapted the nervous system to this capacity is not well understood. Two human-specific amino acid substitutions in the transcription factor forkhead box P2 (FOXP2) are outstanding mechanistic candidates, as they could have been positively selected during human evolution and as FOXP2 is the sole gene to date firmly linked to speech and language development. When these two substitutions are introduced into the endogenous Foxp2 gene of mice (Foxp2 hum ), cortico-basal ganglia circuits are specifically affected. Here we demonstrate marked effects of this humanization of Foxp2 on learning and striatal neuroplasticity. Foxp2 hum/hum mice learn stimulus-response associations faster than their WT littermates in situations in which declarative (i.e., place-based) and procedural (i.e., response-based) forms of learning could compete during transitions toward proceduralization of action sequences. Striatal districts known to be differently related to these two modes of learning are affected differently in the Foxp2 hum/hum mice, as judged by measures of dopamine levels, gene expression patterns, and synaptic plasticity, including an NMDA receptor-dependent form of long-term depression. These findings raise the possibility that the humanized Foxp2 phenotype reflects a different tuning of corticostriatal systems involved in declarative and procedural learning, a capacity potentially contributing to adapting the human brain for speech and language acquisition.T he gene encoding the transcription factor forkhead box P2 (FOXP2) is a promising candidate for investigating the evolutionary basis of human speech and language capabilities. Humans carrying only one functional copy of this transcription factor experience difficulties in learning and performing complex orofacial movements and have receptive and expressive deficits in oral and written language, whereas other cognitive skills are less affected. These speech and language deficits are associated with functional impairments in cortico-basal ganglia and corticocerebellar circuits (1). Since the time that the human and chimpanzee lineages separated, approximately 6 Mya, two amino acid substitutions have occurred in FOXP2, a higher rate of change than expected given its conservation in mammals (2, 3). Mice in which the endogenous Foxp2 gene has been "humanized" for these two amino acid changes (Foxp2 hum/hum mice) exhibit prominent neurochemical, neurophysiological, and neuroanatomical alterations in the striatum and related cortico-basal ganglia circuits (4, 5). These circuits are known to be essential for acquiring habits and other motor and cognitive behaviors (6), including vocal learning in songbirds (7) and speech and language capabilities in humans (8). However, whether learning behavior depending on these circuits is affected in Foxp2 hum/hum mice has so far not been investigated.A key functional distinction has been made between subregions of the striatum that underlie modes o...

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Section: Resultsmentioning

confidence: 99%

“…Behavioral Experiments. Rotarod and tilted running wheel experiments were conducted as previously described (31). For the maze experiments, mice were food-restricted and were habituated to apparatus and reward (chocolate milk).…”

Section: Discussionmentioning

confidence: 99%

Humanized Foxp2 accelerates learning by enhancing transitions from declarative to procedural performance

Schreiweis

Bornschein

Burguière

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

141

136

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“…(Grey box) This line has a missense mutation in exon 14 of the Foxp2 gene; one of 3 exons which encode the DNA-binding domain (dark grey). The mutation causes an arginine to histidine substitution at position 552 which is equivalent to the change found in affected members of the KE family [22 ]. (Blue box) At the cellular level, process length and branch number were reduced in neurites of primary cells isolated from the ganglionic eminences of E16 Foxp2-R552H homozygotes compared to wild-type littermates.…”

Section: Wtmentioning

confidence: 99%

What can mice tell us about Foxp2 function?

French

Fisher

2014

Current Opinion in Neurobiology

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Disruptions of the FOXP2 gene cause a rare speech and language disorder, a discovery that has opened up novel avenues for investigating the relevant neural pathways. FOXP2 shows remarkably high conservation of sequence and neural expression in diverse vertebrates, suggesting that studies in other species are useful in elucidating its functions. Here we describe how investigations of mice that carry disruptions of Foxp2 provide insights at multiple levels: molecules, cells, circuits and behaviour. Work thus far has implicated the gene in key processes including neurite outgrowth, synaptic plasticity, sensorimotor integration and motor-skill learning.

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“…Mice that carry heterozygous mutations equivalent to those in affected members of the KE family have deficits in learning rapid motor sequences, as well as impaired synaptic plasticity in corticostriatal and cerebellar circuits. 21,22 A primary constraint in CAS-genetics and other CAS research-the need for a diagnostically conclusive assessment method-has recently been addressed. 23 The goal of the present study was to use contemporary methods in speech and genetics, to add to the literature the first report of co-occurring 16p11.2 microdeletion syndrome and CAS in two patients.…”

Section: Childhood Apraxia Of Speech (Cas)mentioning

confidence: 99%

Childhood Apraxia of Speech (CAS) in two patients with 16p11.2 microdeletion syndrome

et al. 2012

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We report clinical findings that extend the phenotype of the B550 kb 16p11.2 microdeletion syndrome to include a rare, severe, and persistent pediatric speech sound disorder termed Childhood Apraxia of Speech (CAS). CAS is the speech disorder identified in a multigenerational pedigree ('KE') in which half of the members have a mutation in FOXP2 that co-segregates with CAS, oromotor apraxia, and low scores on a nonword repetition task. Each of the two patients in the current report completed a 2-h assessment protocol that provided information on their cognitive, language, speech, oral mechanism, motor, and developmental histories and performance. Their histories and standard scores on perceptual and acoustic speech tasks met clinical and research criteria for CAS. Array comparative genomic hybridization analyses identified deletions at chromosome 16p11.2 in each patient. These are the first reported cases with well-characterized CAS in the 16p11.2 syndrome literature and the first report of this microdeletion in CAS genetics research. We discuss implications of findings for issues in both literatures.

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

Cited by 261 publications

References 37 publications

Humanized Foxp2 accelerates learning by enhancing transitions from declarative to procedural performance

Humanized Foxp2 accelerates learning by enhancing transitions from declarative to procedural performance

What can mice tell us about Foxp2 function?

Childhood Apraxia of Speech (CAS) in two patients with 16p11.2 microdeletion syndrome

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