FOXP2 regulation of glutamatergic neuron subtypes in the inferior colliculus

About This Grant

Project Summary/Abstract The inferior colliculus (IC) is a crucial auditory processing center in the brain, yet the molecular characterizations of its cell types are not well understood. FOXP2, a transcription factor in the FOXP family, is abundantly expressed in the IC, although its function in the IC is completely unknown. FOXP2 is expressed primarily in glutamatergic neurons of the IC, indicating a potential role in neuronal function for these cell types. FOXP2 mutations are associated with autism, attention-deficit/hyperactivity disorder, and speech and language deficits, but the cellular mechanisms and transcriptional targets regulated by FOXP2 remain elusive. The IC serves as an excellent model region to study FOXP2 due to its well-characterized sensory responses and the availability of easily measured electrophysiological properties and reflexive behaviors. However, this approach is limited by the lack of detailed knowledge about IC cell subtypes and FOXP2 expression in these cells. Our preliminary data using a mouse model of Foxp2 deletion in the IC reveal two findings: 1) altered auditory-motor gating, mirrored in systems-level physiological measurements, reflecting changes in the temporal properties of IC pathways, and 2) single-cell transcriptome analysis that provides the first unbiased categorization of IC cell types together with the identification of the loss of specific glutamatergic subtypes in the absence of FOXP2. We hypothesize that FOXP2 orchestrates transcriptional signaling cascades in a cell type-specific manner, essential for the function of circuits governing auditory-motor gating and perception. We will explore the cell type-specific contributions in the IC using a Foxp2 conditional knockout mouse with three Aims: 1) Determine the transcriptionally defined cell subtypes in the postnatal IC and their gene expression programs regulated by FOXP2; 2) Investigate the role of FOXP2 in the fate determination, survival, morphology and relative proportion of distinct ICC glutamatergic neurons and the overall anatomy of the IC; and 3) Determine the role of FOXP2 in the electrophysiological properties of glutamatergic neurons in the ICC. These aims will elucidate the cell-type- specific roles of FOXP2 in the IC and highlight the contribution of dysfunctional FOXP2 in brain disorders.