Sex-Specific Social Behavior and Amygdala Proteomic Deficits in Foxp2+/− Mutant Mice

Abstract

In humans, mutations in the transcription factor encoding gene, FOXP2, are associated with language and Autism Spectrum Disorders (ASD), the latter characterized by deficits in social interactions. However, little is known regarding the function of Foxp2 in male or female social behavior. Our previous studies in mice revealed high expression of Foxp2 within the medial subnucleus of the amygdala (MeA), a limbic brain region highly implicated in innate social behaviors such as mating, aggression, and parental care. Here, using a comprehensive panel of behavioral tests in male and female Foxp2+/– heterozygous mice, we investigated the role Foxp2 plays in MeA-linked innate social behaviors. We reveal significant deficits in olfactory processing, social interaction, mating, aggressive, and parental behaviors. Interestingly, some of these deficits are displayed in a sex-specific manner. To examine the consequences of Foxp2 loss of function specifically in the MeA, we conducted a proteomic analysis of microdissected MeA tissue. This analyses revealed putative sex differences expression of a host of proteins implicated in neuronal communication, connectivity, and dopamine signaling. Consistent with this, we discovered that MeA Foxp2-lineage cells were responsive to dopamine with differences between males and females. Thus, our findings reveal a central and sex-specific role for Foxp2 in social behavior and MeA function.

Connectivity and molecular profiles of Foxp2‐ and Dbx1‐lineage neurons in the accessory olfactory bulb and medial amygdala

“…Urocortin 3 has been shown to promote preference for social novelty through its action in the MeA (Shemesh et al., 2016), infant‐directed aggression through its function in the perifornical area of the hypothalamus (Autry et al., 2021), and feeding (Stengel & Taché, 2014). This suggests a role for Foxp2+ neurons in these behaviors and is consistent with the role of the Foxp2 gene and Foxp2+ neurons in aggression (Herrero et al., 2021; Lischinsky et al., 2017, 2023). Aside from CARTPT, it is important to note that although lineage restricted, Tac2 , Npy , and Ucn3 are only expressed in a small subset of neurons.…”

“…This suggests a role for Foxp2+ neurons in these behaviors and is consistent with the role of the Foxp2 gene and Foxp2+ neurons in aggression (Herrero et al, 2021;Lischinsky et al, 2017Lischinsky et al, , 2023. Aside from CARTPT, it is important to note that although lineage restricted, Tac2, Npy, and Ucn3 are only expressed in a small subset of neurons.…”

Molecular diversity and connectivity of accessory olfactory system neurons

“…In contrast, of the 10 neuropeptides explored, we found only Ucn3 to be enriched in the Foxp2+ population. Ucn3 is implicated in social novelty preference, infant-directed aggression and feeding (Autry et al, 2021;Shemesh et al, 2016;Stengel & Taché, 2014), suggesting a role for Foxp2+ neurons in these behaviors and consistent with its known role in aggression (Herrero et al, 2021;Lischinsky et al, 2017Lischinsky et al, , 2022.…”

Discovery of 95 PTSD loci provides insight into genetic architecture and neurobiology of trauma and stress-related disorders

“…Together, these top genes show a remarkable convergence with neural network, synaptic plasticity and immune processes implicated in psychiatric disease. Furthermore, CRHR1, 74,75 WNT3, 76,77 and FOXP2, 78,79 among other genes, are implicated in preclinical and clinical work related to stress, fear and threat-processing brain regions thought to underlie the neurobiology of PTSD. These findings largely support existing mechanistic hypotheses, and it will be important to examine how these genes and pathways function in already identified stress-related neural circuits and biological systems.…”