Foxp1 in Forebrain Pyramidal Neurons Controls Gene Expression Required for Spatial Learning and Synaptic Plasticity

Abstract

Genetic perturbations of the transcription factor () are causative for severe forms of autism spectrum disorder that are often comorbid with intellectual disability. Recent work has begun to reveal an important role for FoxP1 in brain development, but the brain-region-specific contributions of Foxp1 to autism and intellectual disability phenotypes have yet to be determined fully. Here, we describe conditional knock-out () male and female mice with loss of Foxp1 in the pyramidal neurons of the neocortex and the CA1/CA2 subfields of the hippocampus. mice exhibit behavioral phenotypes that are of potential relevance to autism spectrum disorder, including hyperactivity, increased anxiety, communication impairments, and decreased sociability. In addition, mice have gross deficits in learning and memory tasks of relevance to intellectual disability. Using a genome-wide approach, we identified differentially expressed genes in the hippocampus of mice associated with synaptic function and development. Furthermore, using magnetic resonance imaging, we uncovered a significant reduction in the volumes of both the entire hippocampus as well as individual hippocampal subfields of mice. Finally, we observed reduced maintenance of LTP in area CA1 of the hippocampus in these mutant mice. Together, these data suggest that proper expression of Foxp1 in the pyramidal neurons of the forebrain is important for regulating gene expression pathways that contribute to specific behaviors reminiscent of those seen in autism and intellectual disability. In particular, Foxp1 regulation of gene expression appears to be crucial for normal hippocampal development, CA1 plasticity, and spatial learning. Loss-of-function mutations in the transcription factor () lead to autism spectrum disorder and intellectual disability. Understanding the potential brain-region-specific contributions of FOXP1 to disease-relevant phenotypes could be a critical first step in the management of patients with these mutations. Here, we report that conditional knock-out () mice with loss of Foxp1 in the neocortex and hippocampus display autism and intellectual-disability-relevant behaviors. We also show that these phenotypes correlate with changes in both the genomic and physiological profiles of the hippocampus in mice. Our work demonstrates that brain-region-specific FOXP1 expression may relate to distinct, clinically relevant phenotypes.

Single-cell analysis of Foxp1-driven mechanisms essential for striatal development

“…Striosomes receive preferential inputs from limbic subcortical regions, including the amygdala and bed nucleus of the stria terminalis 8 ; thus, inputs from these limbic regions targeting striosomes may be disrupted and contribute to the limbic-associated behavioral deficits seen in Foxp1 D1 and Foxp1 DD mice. Additionally, mice with cortical and hippocampal deletion of Foxp1 did not show deficits in cued or contextual fear conditioning 38 .…”

“…To examine the contribution of Foxp1 to striatal development in a cell-type-specific manner, we generated Foxp1 conditional knockout (cKO) mice using BAC-transgenic mice driving Cre expression under the D1-or D2-receptor promoters 36 crossed to Foxp1 flox/flox mice [37][38][39] (Fig. 1a).…”

“…All experiments were performed according to procedures approved by the UT Southwestern Institutional Animal Care and Use Committee. Foxp1 flox/flox mice 72 were provided by Dr. Haley Tucker and backcrossed to C57BL/6J for at least 10 generations to obtain congenic animals as previously described 38,39 . Drd1a-Cre (262Gsat, 030989-UCD) and Drd2-Cre (ER44Gsat, 032108-UCD) mice were obtained from MMRC.…”

Identification of a de novo FOXP1 mutation and incidental discovery of inherited genetic variants contributing to a case of autism spectrum disorder and epilepsy

“…FOXP1 proteins interact with neural stem cells and promote differentiation and migration through repression of the Notch signaling pathway (Braccioli et al, 2017). FOXP1 is also expressed in the developing striatal projection neurons and basal ganglia (Araujo et al, 2017;Tamura, Morikawa, Iwanishi, Hisaoka, & Senba, 2004). Reduction in the striatum and enlargement of the lateral ventricles has been observed in patients with FOXP1 haploinsufficiency (Bacon et al, 2015;Pariani et al, 2009).…”

Integrated Transcriptome Analyses Revealed Key Target Genes in Mouse Models of Autism

“…Interestingly, a significant number of ASD genes have been shown to play important roles in gene expression regulation, including transcriptional factors, chromatin remodeling factors and other types of epigenetic regulators, such as CHD8, FMR1, MECP2, and so on [Alonso-Gonzalez, Rodriguez-Fontenla, & Carracedo, 2018;De Rubeis et al, 2014]. Accordingly, numerous loss of function animal models were generated, especially the mouse models, to recapitulate the disease phenotypes and to explore the underlying molecular mechanisms [Araujo et al, 2017;Arbogast et al, 2018;Caubit et al, 2016;Celen et al, 2017;Cheng et al, 2018;Gabel et al, 2015;Harrington et al, 2016;Huang et al, 2018;Jung et al, 2018;Kong et al, 2014;McGill et al, 2018;Prilutsky et al, 2015;Provenzano et al, 2016;Raman et al, 2018;Scandaglia et al, 2017;Sgado et al, 2013;Suetterlin et al, 2018;Zhao, Goffin, Johnson, & Zhou, 2013]. With these models, RNA-Seq or microarray experiments have been performed in various brain regions to identify the downstream targets of the corresponding ASD genes.…”