Foxp2 Mutations Impair Auditory-Motor Association Learning

Abstract

Heterozygous mutations of the human FOXP2 transcription factor gene cause the best-described examples of monogenic speech and language disorders. Acquisition of proficient spoken language involves auditory-guided vocal learning, a specialized form of sensory-motor association learning. The impact of etiological Foxp2 mutations on learning of auditory-motor associations in mammals has not been determined yet. Here, we directly assess this type of learning using a newly developed conditioned avoidance paradigm in a shuttle-box for mice. We show striking deficits in mice heterozygous for either of two different Foxp2 mutations previously implicated in human speech disorders. Both mutations cause delays in acquiring new motor skills. The magnitude of impairments in association learning, however, depends on the nature of the mutation. Mice with a missense mutation in the DNA-binding domain are able to learn, but at a much slower rate than wild type animals, while mice carrying an early nonsense mutation learn very little. These results are consistent with expression of Foxp2 in distributed circuits of the cortex, striatum and cerebellum that are known to play key roles in acquisition of motor skills and sensory-motor association learning, and suggest differing in vivo effects for distinct variants of the Foxp2 protein. Given the importance of such networks for the acquisition of human spoken language, and the fact that similar mutations in human FOXP2 cause problems with speech development, this work opens up a new perspective on the use of mouse models for understanding pathways underlying speech and language disorders.

Components of the Language-Ready Brain

“…Interestingly, the human version of Foxp2 has strong effects on the plasticity of the striaum and accelerates learning when introduced into mice (Schreiweis et al, 2014). Mice with certain point mutations in one copy of Foxp2, including those that cause developmental verbal dyspraxia in humans, are developmentally delayed, somatically weak, and have impaired auditory-motor association learning owing to strongly altered activity in the striatal circuits, but they make the expected range of acoustically normal vocalizations (Gaub et al, 2010;Kurt et al, 2012). These studies collectively give a more robust view of this gene's role in vocalization than would be possible using a single species.…”

Intronic miRNA miR-3666 Modulates its Host Gene FOXP2 Functions in Neurodevelopment and May Contribute to Pathogenesis of Neurological Disorders Schizophrenia and Autism

“…Although FOXP2 has extensive expression in the developing brain, a quite low expression in the adult brain [42] suggests that the expression of FOXP2 is developmentally regulated. Mutational analysis in several studies [43,44,45] have demonstrated the association of non-functional FOXP2 with motor dysfunction, cerebellar abnormalities and early postnatal lethality. In an experiment that studied miRNA expression during the process of neural differentiation using an RA (retinoic acid)-induced embryonal carcinoma NTera2/D1 (NT2) cell line, miR-3666 was observed to continue being expressed in fully differentiated NT2-derived postmitotic neurons and/or NT2-derived astrocytes.…”

A Molecular Genetic Perspective on Speech and Language

“…The discovery of disturbed striatal plasticity during learning of a complex motor task in mice is intriguing because neuroimaging studies of humans with the same mutation have independently suggested striatal dysfunction as a potential core feature of their disorder (Liegeois et al, 2003(Liegeois et al, , 2011Vargha-Khadem et al, 1998;Watkins, Dronkers, et al, 2002). Another behavioral study of this mouse model demonstrated reduced performance on a learning task in which the animals had to associate auditory signals with motor outputs (Kurt, Fisher, & Ehret, 2012). This last investigation also compared the learning dynamics with those of another mouse line that carried a different etiological mutation of Foxp2, reporting that the degree of impairment seemed to be affected by the type of mutation (Kurt et al, 2012).…”