Foxp1 in Forebrain Pyramidal Neurons Controls Gene Expression Required for Spatial Learning and Synaptic Plasticity
Open accessAbstract
Genetic perturbations of the transcription factor Forkhead Box P1(FOXP1) 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 Foxp1 conditional knock-out (Foxp1cKO) male and female mice with loss of Foxp1 in the pyramidal neurons of the neocortex and the CA1/CA2 subfields of the hippocampus.Foxp1cKO mice exhibit behavioral phenotypes that are of potential relevance to autism spectrum disorder, including hyperactivity, increased anxiety, communication impairments, and decreased sociability. In addition,Foxp1cKO 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 Foxp1cKO 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 Foxp1cKO 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. SIGNIFICANCE STATEMENT Loss-of-function mutations in the transcription factor Forkhead Box P1(FOXP1) 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 Foxp1 conditional knock-out (Foxp1cKO) 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 Foxp1cKO mice. Our work demonstrates that brain-region-specific FOXP1 expression may relate to distinct, clinically relevant phenotypes.
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Foxp1 displays mouse-human conservation of local genome architecture and loops to several autism spectrum disorder-associated single-nucleotide variants and activity-induced enhancers.
“Foxp1, which has been found previously to regulate brain development and synaptic plasticity44, displays remarkable mouse–human conservation of local genome architecture, and loops to several ASD-associated SNVs (Extended Data Fig. 10c) and activity-induced enhancers”
From Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression (2020) · cites this paper as [44]
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Integrated Transcriptome Analyses Revealed Key Target Genes in Mouse Models of Autism
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Differential Regulation of the BDNF Gene in Cortical and Hippocampal Neurons
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Prenatal Sex Hormone Exposure Is Associated with the Development of Autism Spectrum Disorder
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Circular RNA Circ_ANKMY2 Regulates Temporal Lobe Epilepsy Progression via the miR-106b-5p/FOXP1 Axis
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Genomic Strategies for Understanding the Pathophysiology of Autism Spectrum Disorder
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Self-citationTranscription factor Foxp1 is essential for the induction of choroidal neovascularization
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Critical periods and Autism Spectrum Disorders, a role for sleep
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- Authors
- Araujo, D. J., Toriumi, K., Escamilla, C. O., Kulkarni, A., Anderson, A. G., Harper, M., Usui, N., Ellegood, J., Lerch, J. P., Birnbaum, S. G., Tucker, H. O., Powell, C. M., & Konopka, G.
- Affiliations
- Tokyo Metropolitan Institute of Medical Science (JP)
- Hospital for Sick Children (CA)
- University of Toronto (CA)
- The University of Texas Southwestern Medical Center (US)
- The University of Texas at Austin (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2017-10-04
- Volume
- 37
- Issue
- 45
- Pages
- 10917-10931
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC5678023
- OpenAlex
- W2762946595
- Cited by
- 73
- References
- 77
- Citations by year
- 2026: 4 · 2025: 14 · 2024: 8 · 2023: 6 · 2022: 9 · 2021: 14 · 2020: 6 · 2019: 7 · 2018: 3 · 2017: 1
- FWCI
- 3.09
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation (2013162469)
- Simons Foundation (401220)
- Uehara Memorial Foundation
- Fondation Brain Canada
- Simons Foundation Autism Research Initiative (401220)
- National Institutes of Health
- Japan Society for the Promotion of Science (26870878)
- National Institute of Mental Health (R01MH102603, T32MH076690, T32-MH76690, R01MH093697)
- National Institute on Deafness and Other Communication Disorders (R01DC014702)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD069560)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- FOXP1, autism spectrum disorder, intellectual disability, pyramidal neurons, hippocampus, neocortex, spatial learning, synaptic plasticity, long-term potentiation, CA1, hippocampal development, hippocampal volume, gene expression, conditional knockout mice, hyperactivity, anxiety, sociability, communication disorders
- MeSH terms
- Autism Spectrum Disorder, Animals, Behavior, Animal, Female, Learning Disabilities, Male, Memory Disorders, Mice, Inbred C57BL, Neuronal Plasticity, Repressor Proteins, Synapses, Vocalization, Animal, Gene Expression, Pyramidal Cells, Mice, Knockout, Neocortex, Mice, Forkhead Transcription Factors, CA1 Region, Hippocampal, Spatial Learning
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