Increased Training Intensity Induces Proper Membrane Localization of Actin Remodeling Proteins in the Hippocampus Preventing Cognitive Deficits: Implications for Fragile X Syndrome
Abstract
Behavioral intervention therapy has proven beneficial in the treatment of autism and intellectual disabilities (ID), raising the possibility of certain changes in molecular mechanisms activated by these interventions that may promote learning. Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by autistic features and intellectual disability and can serve as a model to examine mechanisms that promote learning. FXS results from mutations in the fragile X mental retardation 1 gene (Fmr1) that prevents expression of the Fmr1 protein (FMRP), a messenger RNA (mRNA) translation regulator at synapses. Among many other functions, FMRP organizes a complex with the actin cytoskeleton-regulating small Rho GTPase Rac1. As in humans, Fmr1 KO mice lacking FMRP display autistic-like behaviors and deformities of actin-rich synaptic structures in addition to impaired hippocampal learning and synaptic plasticity. These features have been previously linked to proper function of actin remodeling proteins that includes Rac1. An important step in Rac1 activation and function is its translocation to the membrane, where it can influence synaptic actin cytoskeleton remodeling during hippocampus-dependent learning. Herein, we report that Fmr1 KO mouse hippocampus exhibits increased levels of membrane-bound Rac1, which may prevent proper learning-induced synaptic changes. We also determine that increasing training intensity during fear conditioning (FC) training restores contextual…
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Rac1 is a converging factor downstream of numerous proteins encoded by high-risk ASD genes.
“Rac1 has been identified as a converging factor downstream of numerous proteins encoded by high-risk ASD genes, such as SHANK 4–6, FMR1 (fragile X mental retardation-1) 7, 8, NRXN 9, and AUTS2 10.”
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 [8]
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Guo, D., Peng, Y., Wang, L., Sun, X., Wang, X., Liang, C., Yang, X., Li, S., Xu, J., Ye, W.-C., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-019-0472-7 · Cited by 102 · see citing works
- Authors
- Martinez, L. A., & Tejada-Simon, M. V.
- Affiliations
- University of Houston (US)
- Corresponding author
- Tejada-Simon, Maria Victoria
- Venue
- Molecular Neurobiology
- Published
- 2017-07-08
- Volume
- 55
- Issue
- 6
- Pages
- 4529-4542
- ISSN
- 0893-7648 (ISSN-L)
- 1559-1182
- OpenAlex
- W2725220212
- Cited by
- 13
- References
- 12
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 1 · 2020: 2 · 2019: 3 · 2018: 1 · 2017: 1
- FWCI
- 1.27
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Neurobiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- FRAXA Research Foundation
- Fondation Jérôme Lejeune
- 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 › Memory and Neural Mechanisms
- Keywords
- fragile X syndrome, FMRP, Fmr1 knockout mice, Rac1, actin cytoskeleton, membrane localization, hippocampus, fear conditioning, contextual memory, long-term potentiation, exercise intensity, synaptic plasticity, intellectual disability, autism spectrum disorder, cognitive impairment
- MeSH terms
- Actins, Animals, Cell Membrane, Conditioning, Psychological, Cytosol, Fear, Female, Fragile X Syndrome, Hippocampus, Humans, Male, Memory, Theta Rhythm, Long-Term Potentiation, Mice, Knockout, rac1 GTP-Binding Protein, Fragile X Messenger Ribonucleoprotein 1, p21-Activated Kinases, Cognitive Dysfunction
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