Knockdown of FoxP2 alters spine density in Area X of the zebra finch

Abstract

Mutations in the gene encoding the transcription factor FoxP2 impair human speech and language. We have previously shown that deficits in vocal learning occur in zebra finches after reduction of FoxP2 in Area X, a striatal nucleus involved in song acquisition. We recently showed that FoxP2 is expressed in newly generated spiny neurons (SN) in adult Area X as well as in the ventricular zone (VZ) from which the SN originates. Moreover, their recruitment to Area X increases transiently during the song learning phase. The present report therefore investigated whether FoxP2 is involved in the structural plasticity of Area X. We assessed the proliferation, differentiation and morphology of SN after lentivirally mediated knockdown of FoxP2 in Area X or in the VZ during the song learning phase. Proliferation rate was not significantly affected by knockdown of FoxP2 in the VZ. In addition, FoxP2 reduction both in the VZ and in Area X did not affect the number of new neurons in Area X. However, at the fine-structural level, SN in Area X bore fewer spines after FoxP2 knockdown. This effect was even more pronounced when neurons received the knockdown before differentiation, i.e. as neuroblasts in the VZ. These results suggest that FoxP2 might directly or indirectly regulate spine dynamics in Area X and thereby influence song plasticity. Together, these data present the first evidence for a role of FoxP2 in the structural plasticity of dendritic spines and complement the emerging evidence of physiological synaptic plasticity in FoxP2 mouse models.

Components of the Language-Ready Brain

“…It was then established that this gene is highly conserved from reptiles to humans, but especially among mammals, with strong evidence for recent selection in the human lineage (Enard et al, 2002;Scharff and Haesler, 2005). Due to current technological limitations, RNAi-mediated knockdown using a lentivral vector has been used to study the effect of reduced Foxp2 expression in Area X of the zebra finch brain, rather than a transgenic approach Schulz et al, 2010). In mice, heterozygous and homozygous Foxp2 knockouts as well as humanized knockins have been studied, and a mouse model has been developed with a conditional null (floxed) allele, allowing crosses to transgenic lines expressing Cre drivers for tissue-and timespecific conditional knockouts (French et al, 2007).…”

“…In mice, heterozygous and homozygous Foxp2 knockouts as well as humanized knockins have been studied, and a mouse model has been developed with a conditional null (floxed) allele, allowing crosses to transgenic lines expressing Cre drivers for tissue-and timespecific conditional knockouts (French et al, 2007). Knockdown (in finches) or haploinsufficiency (in mice) of Foxp2 leads to altered or inaccurate vocalizations (Shu et al, 2005;, and in the finch this is associated with the altered density of spiny neurons in Area X (Schulz et al, 2010). 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).…”

Insights into the Genetic Foundations of Human Communication

“…In juvenile birds, FoxP2 levels are increased in Area X, a striatal nucleus involved in vocal learning, during the critical period for song-learning (Haesler et al 2004) and are downregulated when adult males are practising their songs without directing them to a female (Miller et al 2008;Teramitsu and White 2006;Teramitsu et al 2010). Furthermore, viral-based knockdown of FoxP2 in Area X results in reduced spine density of medium spiny neurons (Schulz et al 2010) and impairs song-learning (Haesler et al 2007;Murugan et al 2013). Thus, both investigations of vocal learning in songbirds and of motor-skill learning in mouse models point to roles for FOXP2 in neural plasticity.…”

A Molecular Genetic Perspective on Speech and Language

“…In a landmark paper, Haesler and colleagues (2007) reported that such FoxP2 knockdown in Area X (but not surrounding areas) during the developmental period of song acquisition led to incomplete and inaccurate imitation of tutor song. Further studies of knockdown birds indicate that FoxP2 loss yields reduced density for dendritic spines of spiny neurons (Schulz, Haesler, Scharff, & Rochefort, 2010) and interferes with dopamine modulation of activity propagation in a corticostriatal pathway involved in song variability (Murugan, Harward, Scharff, & Mooney, 2013). As with the mouse models, neural plasticity in striatal circuitry emerges as a common theme associated with this gene (Murugan et al, 2013;Schulz et al, 2010).…”

“…Further studies of knockdown birds indicate that FoxP2 loss yields reduced density for dendritic spines of spiny neurons (Schulz, Haesler, Scharff, & Rochefort, 2010) and interferes with dopamine modulation of activity propagation in a corticostriatal pathway involved in song variability (Murugan, Harward, Scharff, & Mooney, 2013). As with the mouse models, neural plasticity in striatal circuitry emerges as a common theme associated with this gene (Murugan et al, 2013;Schulz et al, 2010). There is insufficient space available in this chapter to give a full account of all the relevant songbird studies; for further information on this burgeoning area of work, the interested reader is referred to reviews by Bolhuis et al (2010), Petri (2011), andWohlgemuth et al (2014).…”