Whether FoxP2 influences not only the function but also the integration of new neurons into existing circuits is still an open question. Recently we showed that new MSNs mature and participate in singing activity – as measured by immediate early gene activation – within a timeframe of six weeks 34. FoxP2 high MSNs colocalize more frequently with a marker for new neurons than FoxP2 low MSNs 24. Adult Area X constantly receives new MSNs that originate at the ventricular zone 28– 33. The authors hypothesized that the difference might be due to the neuronal age. Both subtypes are not equally affected by singing the density of FoxP2 high MSNs is not measurably different after singing, contrary to the decreasing density of FoxP2 low MSNs 24. How does singing affect FoxP2 expression at the cellular level? Medium spiny neurons (MSNs), the most abundant cell type in the avian striatum, predominantly express FoxP2 at low levels (FoxP2 low) while a subset expresses FoxP2 at very high levels (FoxP2 high). This relationship is missing in deafened birds, pointing to an important role of auditory feedback for singing-driven FoxP2 down regulation 27. Singing decreases overall FoxP2 levels in Area X but not in the surrounding striatum and the degree of FoxP2 down regulation correlates with the amount of produced song 25– 27. FoxP2 expression levels in Area X transiently increase during song learning but are lower in adults 7, 24. Further evidence for the biological relevance of tight regulation of FoxP2 expression levels comes from the following studies. Additional effects of Foxp2 and its disruption on the embryonic development and the function of neural circuits have been described in mice 14– 23. In addition, altered FoxP2 levels in adult Area X affect the dopaminergic modulation of corticostriatal signaling important to song variability and affect song maintenance 12, 13, stressing the fact that tight regulation of FoxP2 expression is a prerequisite for correct neural transmission in differentiated neural circuits. The core-phenotype of DVD consists of altered precision, consistency and sequencing of movements underlying speech in the absence of neuromuscular deficits 11. This phenotype bears similarities to the specific speech deficits called developmental verbal dyspraxia, DVD (or childhood apraxia of speech), that patients carrying FOXP2 mutations suffer from. Moreover, genetic manipulations of FoxP2 expression levels in the striatal song nucleus Area X during the critical phase of song learning lead to inaccurate and incomplete imitation of the tutor’s song and more variable vocal production 3, 8– 10. The FoxP2 protein coding sequence is highly conserved between humans and songbirds as are the brain expression patterns, notably in the cerebellum and striatum 5– 7. Studying the relationship between FoxP2 and vocal learning in songbirds may inform the neurogenetic mechanism underlying the speech deficits in patients carrying FOXP2 mutations for the following reasons. Because songbirds – like humans – need to learn most of their communicative vocalizations, they offer a unique model to study the role of FoxP2 (for nomenclature FOXP2/FoxP2 see Methods) for vocal learning and for the maintenance of learned vocalizations as adults 4. Heterozygous FOXP2 mutations in humans affect both the coordination of fine orofacial movements and language perception 1– 3. The forkhead box P2 transcription factor (FOXP2) is linked to speech and language disorders. Together, our data suggest that dynamic FoxP2 levels in new MSNs shape their morphology during maturation and their incorporation into a neural circuit that enables the maintenance and social modulation of adult birdsong. In addition, FoxP2 expression levels correlated positively with nucleus size of new MSNs. ![]() However, new FoxP2 high MSNs had more complex dendrites, higher spine density and more mushroom spines than new FoxP2 low MSNs. Contrary to our expectation, FoxP2 protein levels did not predict whether new MSNs were active during singing, assayed via immediate early gene expression. Because Area X receives many new neurons throughout adulthood, we hypothesized that the FoxP2 high MSNs are newly recruited neurons, not yet integrated into the local Area X circuitry and thus not active during singing. However, some Area X medium spiny neurons (MSNs) express FoxP2 at high levels (FoxP2 high MSNs) and singing does not change this. Overall FoxP2 protein levels in Area X are low in adult zebra finches and decrease further with singing. In songbirds, experimentally altered FoxP2 expression levels in the striatal song nucleus Area X impair vocal learning and song production. FOXP2 mutations are associated with specific speech and language impairments. ![]() The transcription factor FOXP2 is crucial for the formation and function of cortico-striatal circuits.
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