Synaptic P-Rex1 signaling regulates hippocampal long-term depression and autism-like social behavior
Open accessAbstract
Autism spectrum disorders (ASDs) are a group of highly inheritable mental disorders associated with synaptic dysfunction, but the underlying cellular and molecular mechanisms remain to be clarified. Here we report that autism in Chinese Han population is associated with genetic variations and copy number deletion of P-Rex1 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 1). Genetic deletion or knockdown of P-Rex1 in the CA1 region of the hippocampus in mice resulted in autism-like social behavior that was specifically linked to the defect of long-term depression (LTD) in the CA1 region through alteration of AMPA receptor endocytosis mediated by the postsynaptic PP1α (protein phosphase 1α)-P-Rex1-Rac1 (Ras-related C3 botulinum toxin substrate 1) signaling pathway. Rescue of the LTD in the CA1 region markedly alleviated autism-like social behavior. Together, our findings suggest a vital role of P-Rex1 signaling in CA1 LTD that is critical for social behavior and cognitive function and offer new insight into the etiology of ASDs.
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Restoration of normal Rac1 activity or its downstream effectors corrects autism-like behaviors and synaptic abnormalities.
“Supporting this notion, restoration of normal activity of Rac1 or its downstream effectors was demonstrated as a successful approach for correcting autism-like behaviors and synaptic abnormalities 12–15.”
From Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function. (2021) · cites this paper as [14]
Cites
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“Thus, we have elucidated a synaptic mechanism underlying the deficit in social recognition induced by P-Rex1 disruption and the cognitive dysfunction associated with ASDs.”
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BackgroundRegulation of Synaptic Strength by Protein Phosphatase 1
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Self-citation
- Authors
- Li, J., Chai, A., Wang, L., Ma, Y., Wu, Z., Yu, H., Mei, L., Lu, L., Zhang, C., Yue, W., Xu, L., Rao, Y., & Zhang, D.
- Affiliations
- Peking University (CN)
- Chinese University of Hong Kong (HK)
- Institute of Mental Health, Sixth Hospital of Peking University, Beijing 100191, China;
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-11-30
- Volume
- 112
- Issue
- 50
- Pages
- E6964-72
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4687539
- OpenAlex
- W2188820648
- Cited by
- 75
- References
- 12
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 6 · 2023: 5 · 2022: 10 · 2021: 10 · 2020: 5 · 2019: 6 · 2018: 5 · 2017: 7 · 2016: 4
- FWCI
- 3.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- Ministry of Science and Technology of the People's Republic of China (2010CB833905, 2013CB835103)
- National Natural Science Foundation of China (91232305, 81471360, 81222017, 81471383, 81221002, 81501183)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Keywords
- P-Rex1, autism spectrum disorder, long-term depression, hippocampal CA1, AMPA receptor endocytosis, PP1α, Rac1, phosphatidylinositol 3,4,5-trisphosphate, copy number deletion, genetic variation, synaptic dysfunction, Han Chinese
- MeSH terms
- Animals, Autistic Disorder, Humans, Social Behavior, Synapses, Signal Transduction, Receptors, N-Methyl-D-Aspartate, Mice, Knockout, Guanine Nucleotide Exchange Factors, Long-Term Synaptic Depression, Mice, CA1 Region, Hippocampal, DNA Copy Number Variations
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