Prefrontal Cortex Dysfunction in Fragile X Mice Depends on the Continued Absence of Fragile X Mental Retardation Protein in the Adult Brain
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Fragile X Syndrome (FX) is generally considered a developmental disorder, arising from a mutation that disrupts the transcription of Fragile X Mental Retardation Protein (FMRP). However, FMRP regulates the transcription of other proteins and participates in an unknown number of protein–protein interactions throughout life. In addition to known developmental issues, it is thus likely that some dysfunction is also due to the ongoing absence of FMRP. Dissociating dysfunction due to developmental dysregulation from dysfunction due to the continued absence of FMRP is necessary to understand the different roles of FMRP and to treat patients effectively throughout life. We show here that FX model mice display substantial deficits in a PFC-dependent task. We then use conditional knock-out mice to eliminate FMRP only in the PFC alone of adult mice. We observe an increase in the proportion of nonlearners and a delay in the onset of learning in both FX and conditional knock-out mice. The results suggest that these deficits (1) are due to the absence of FMRP in the PFC alone and (2) are not the result of developmental dysregulation. Furthermore, PFC-associated deficits are rescued by initiating production of FMRP in adult conditional restoration mice, suggesting that PFC dysfunction may persist as long as FMRP is absent and therefore can be rescued after development. The data suggest that it is possible to dissociate the roles of FMRP in neural function from developmental dysregulation, and that PFC function can be restored in the adult FX brain. SIGNIFICANCE STATEMENT The absence of Fragile X Mental Retardation Protein (FMRP) from birth results in developmental disabilities and lifelong impairments. We show here that in mouse models PFC dysfunction in Fragile X Syndrome (FX) can be attributed to the continued absence of FMRP from the PFC, independent of FMRP status during development. Furthermore, initiation of FMRP production in the PFC of adult FX animals rescues PFC function. The results suggest that at least some FX-specific neurological defects can be rescued in the adult FX brain after development.
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In Fragile X syndrome, many behavioral and cognitive deficits can be attributed, at least in part, to prefrontal dysfunction.
“It is clear that in FX the many behavioral and cognitive deficits can be attributed, at least in part, to prefrontal dysfunction.”
From Development of prefrontal cortex (2022) · cites this paper as [266]
Some aspects of Fragile X syndrome could be rescued in an animal model where FMRP production was initiated in the mutant PFC.
“Some of these aspects could be rescued in an animal model where FMRP production was initiated in the mutant PFC [266].”
From Development of prefrontal cortex (2022) · cites this paper as [266]
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Polygenic risk scores for schizophrenia are associated with oculomotor endophenotypes
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Associations Between Altered Auditory EEG Markers and Clinical Impairments in Fragile X Syndrome
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- Authors
- Siegel, J. J., Chitwood, R. A., Ding, J. M., Payne, C., Taylor, W., Gray, R., Zemelman, B. V., & Johnston, D.
- Affiliations
- The University of Texas at Austin (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2017-06-26
- Volume
- 37
- Issue
- 31
- Pages
- 7305-7317
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6596701
- OpenAlex
- W2688572985
- Cited by
- 27
- References
- 71
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 6 · 2020: 2 · 2019: 5 · 2018: 5
- FWCI
- 2.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- FRAXA Research Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Keywords
- fragile X syndrome, FMRP, prefrontal cortex, conditional knockout mice, learning deficits, developmental dysregulation
- MeSH terms
- Animals, Cognition Disorders, Fragile X Syndrome, Male, Mice, Inbred C57BL, Prefrontal Cortex, Mice, Knockout, Mice, Fragile X Messenger Ribonucleoprotein 1
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