Diminished FoxP2 Levels Affect Dopaminergic Modulation of Corticostriatal Signaling Important to Song Variability

Abstract

Summary Mutations of the FOXP2 gene impair speech and language development in humans and shRNA-mediated suppression of the avian orthologue FoxP2 disrupts song learning in juvenile zebra finches. How diminished FoxP2 levels affect vocal control and alter the function of neural circuits important to learned vocalizations remains unclear. Here we show that FoxP2 knockdown in the songbird striatum disrupts developmental and social modulation of song variability. Recordings in anaesthetized birds show that FoxP2 knockdown interferes with D1R-dependent modulation of activity propagation in a corticostriatal pathway important to song variability, an effect that may be partly attributable to reduced D1R and DARPP-32 protein levels. Furthermore, recordings in singing birds reveal that FoxP2 knockdown prevents social modulation of singing-related activity in this pathway. These findings show that reduced FoxP2 levels interfere with the dopaminergic modulation of vocal variability, which may impede song and speech development by disrupting reinforcement learning mechanisms.

Behavior-Linked FoxP2 Regulation Enables Zebra Finch Vocal Learning

“…These learning deficits emerged early and persisted into adulthood because FoxP2ϩ birds failed to adaptively modify their songs to produce a copy of their tutors' songs. Interestingly, these results are not directly opposite to those found following knockdown of FoxP2 (Haesler et al, 2007; Murugan et al, 2013), providing support for the importance of behavior-driven cycling in FoxP2 expression in vocal learning.…”

“…Samples were then subjected to electrophoresis, electroblotted onto PVDF membranes (Millipore) for 4 h at 400 mA, and analyzed with rabbit antibody against FoxP2 (1:500, Millipore, ABE73; Miller et al, 2008), mouse antibody to GAPDH (1: 30,000, Millipore, MAB374;Miller et al, 2008), and a rabbit antibody to DARPP-32 (1:5000, Abcam, ab1855; Murugan et al, 2013). Finally, blots were probed with horseradish peroxidase-conjugated anti-rabbit IgG (1: 2000 dilution) and anti-mouse IgG (1:10,000 dilution; GE Healthcare Pharmacia Biotech).…”

What can mice tell us about Foxp2 function?

“…In songbirds, FoxP2 knockdown in striatal Area X of juvenile zebra finches results in inaccurate imitation of the song of a tutor [51]. A recent study [52 ] extended the findings to adult birds, where reduced FoxP2 levels led to disrupted social modulation of song variability. FoxP2 depletion disrupted activity propagation through the anterior forebrain pathway (analogous to the mammalian basal ganglia-thalamocortical pathway), rendering it insensitive to DRD1-mediated signalling.…”

Next stop: Language. The ‘FOXP2’ gene’s journey through time

“…Follow up experiments by us and other researchers have identified factors that regulate FoxP2 expression and cellular/ behavioral consequences of its action (Condro & White, 2014;Wohlgemuth, Adam, & Scharff, 2014). These and other studies have firmly established that FoxP2 has two roles, one in neural development and an «on line» function in already developed neural circuits (Murugan, Harward, Scharff, & Mooney, 2013). …”