Sensorimotor gating abnormalities in young males with fragile X syndrome and Fmr1-knockout mice.
Abstract
Fragile X syndrome (FXS) is the most common single gene (FMR1) disorder affecting cognitive and behavioral function in humans. This syndrome is characterized by a cluster of abnormalities including lower IQ, attention deficits, impairments in adaptive behavior and increased incidence of autism. Here, we show that young males with FXS have profound deficits in prepulse inhibition (PPI), a basic marker of sensorimotor gating that has been extensively studied in rodents. Importantly, the magnitude of the PPI impairments in the fragile X children predicted the severity of their IQ, attention, adaptive behavior and autistic phenotypes. Additionally, these measures were highly correlated with each other, suggesting that a shared mechanism underlies this complex phenotypic cluster. Studies in Fmr1-knockout mice also revealed sensorimotor gating and learning abnormalities. However, PPI and learning were enhanced rather than reduced in the mutants. Therefore, these data show that mutations of the FMR1 gene impact equivalent processes in both humans and mice. However, since these phenotypic changes are opposite in direction, they also suggest that murine compensatory mechanisms following loss of FMR1 function differ from those in humans.
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Auditory hypersensitivity is also evident in Fmr1 KO mice, which exhibit increased susceptibility to audiogenic seizures and abnormal auditory startle.
“Auditory hypersensitivity is also evident in Fmr1 knockout (KO) mice, a mouse model of FXS, which exhibit increased susceptibility to audiogenic seizures (Musumeci et al., 2000) and abnormal auditory startle (Frankland et al., 2004).”
From The Perineuronal ‘Safety’ Net? Perineuronal Net Abnormalities in Neurological Disorders (2018) · cites this paper as Frankland et al., 2004
Cites
Verkerk, A. J. M. H., Pieretti, M., Sutcliffe, J. S., Fu, Y.-H., Kuhl, D. P. A., Pizzuti, A., Reiner, O., Richards, S., Victoria, M. F., Zhang, F., et al. (1991) · Cell · doi:10.1016/0092-8674(91)90397-h · Cited by 3,481 · see citing works
Vineland Adaptive Behavior Scales
Sparrow, S. S. (2010) · Springer eBooks · doi:10.1007/978-0-387-79948-3_1602 · Cited by 1,974 · see citing works
BRAFF, D. L., Geyer, M. A., & Swerdlow, N. R. (2001) · Psychopharmacology · doi:10.1007/s002130100810 · Cited by 1,701 · see citing works
Goal-directed instrumental action: contingency and incentive learning and their cortical substrates
Balleine, B. W., & Dickinson, A. (1998) · Neuropharmacology · doi:10.1016/s0028-3908(98)00033-1 · Cited by 1,541 · see citing works
Self-citationGeyer, M. A., Krebs-Thomson, K., Braff, D. L., & Swerdlow, N. R. (2001) · Psychopharmacology · doi:10.1007/s002130100811 · Cited by 1,484 · see citing works
Autism screening questionnaire: diagnostic validity
Berument, S. K., Rutter, M., Lord, C., Pickles, A., & Bailey, A. (1999) · British Journal of Psychiatry · doi:10.1192/bjp.175.5.444 · Cited by 1,464 · see citing works
The Structure and Organization of Memory
Squire, L. R., Knowlton, B. J., & Musen, G. (1993) · Annual Review of Psychology · doi:10.1146/annurev.ps.44.020193.002321 · Cited by 1,121 · see citing works
Kaufman Brief Intelligence Test
(2012) · Springer eBooks · doi:10.1007/springerreference_183806 · Cited by 1,089 · see citing works
Fmr1 knockout mice: A model to study fragile X mental retardation
THEDUTCHBELGIANFRAGILEXCONSOR (1994) · Cell · doi:10.1016/0092-8674(94)90569-x · Cited by 1,075 · see citing works
Feng, Y., Absher, D., Eberhart, D. E., Brown, V., Malter, H. E., & Warren, S. T. (1997) · Molecular Cell · doi:10.1016/s1097-2765(00)80012-x · Cited by 511 · see citing works
A Decade of Molecular Studies of Fragile X Syndrome
O'Donnell, W. T., & Warren, S. T. (2002) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.25.112701.142909 · Cited by 481 · see citing works
Fragile X mice develop sensory hyperreactivity to auditory stimuli
Chen, L., & Toth, M. (2001) · Neuroscience · doi:10.1016/s0306-4522(01)00036-7 · Cited by 345 · see citing works
Synaptic regulation of protein synthesis and the fragile X protein
Greenough, W. T., Klintsova, A. Y., Irwin, S. A., Galvez, R., Bates, K. E., & Weiler, I. J. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.141145998 · Cited by 317 · see citing works
Hagerman, R. J. (2002) · doi:10.56021/9780801868436 · Cited by 299 · see citing works
Mouse genetic models for prepulse inhibition: an early review
Geyer, M. A., McIlwain, K. L., & Paylor, R. E. (2002) · Molecular Psychiatry · doi:10.1038/sj.mp.4001159 · Cited by 289 · see citing works
(Over)correction of FMR1 deficiency with YAC transgenics: behavioral and physical features
Peier, A. M. (2000) · Human Molecular Genetics · doi:10.1093/hmg/9.8.1145 · Cited by 285 · see citing works
Kaufman Brief Intelligence Test
Hildman, L. K., Friedberg, P. M., & Wright, P. M. (1993) · Journal of Psychoeducational Assessment · doi:10.1177/073428299301100115 · Cited by 245 · see citing works
Mildly impaired water maze performance in maleFmr1 knockout mice
D'Hooge, R., Nagels, G., Franck, F., Bakker, C. E., Reyniers, E., Storm, K., Kooy, R. F., Oostra, B. A., Willems, P. J., & De Deyn, P. P. (1997) · Neuroscience · doi:10.1016/s0306-4522(96)00224-2 · Cited by 208 · see citing works
New insights into fragile X syndrome: from molecules to neurobehaviors
Jin, P., & Warren, S. T. (2003) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(03)00033-1 · Cited by 203 · see citing works
Differential expression of FMR1, FXR1 and FXR2 proteins in human brain and testis
Tamanini, F. (1997) · Human Molecular Genetics · doi:10.1093/hmg/6.8.1315 · Cited by 198 · see citing works
Fmr1 knockout mouse has a distinctive strain-specific learning impairment
Dobkin, C., Rabe, A., Dumas, R., El Idrissi, A., Haubenstock, H., & Ted Brown, W. (2000) · Neuroscience · doi:10.1016/s0306-4522(00)00292-x · Cited by 179 · see citing works
Nielsen, D. M., Derber, W. J., McClellan, D. A., & Crnic, L. S. (2002) · Brain Research · doi:10.1016/s0006-8993(01)03309-1 · Cited by 154 · see citing works
Dam, D. V., D’Hooge, R., Hauben, E., Reyniers, E., Gantois, I., Bakker, C. E., Oostra, B. A., Kooy, R. F., & Deyn, P. P. D. (2000) · Behavioural Brain Research · doi:10.1016/s0166-4328(00)00296-5 · Cited by 145 · see citing works
Mackeprang, T., Kristiansen, K. T., & Glenthoj, B. Y. (2002) · Biological Psychiatry · doi:10.1016/s0006-3223(02)01409-9 · Cited by 144 · see citing works
Prepulse inhibition of startle and the neurobiology of primary nocturnal enuresis
Ornitz, E. M., RUSSELL, A. T., Hanna, G. L., Gabikian, P., Gehricke, J.-G., Song, D., & Guthrie, D. (1999) · Biological Psychiatry · doi:10.1016/s0006-3223(98)00205-4 · Cited by 125 · see citing works
Self-citationKnockout mouse model for Fxr2: a model for mental retardation
Bontekoe, C. J. M. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.5.487 · Cited by 120 · see citing works
Effect of d -amphetamine on prepulse inhibition of the startle reflex in humans
Hutchison, K. E., & Swift, R. M. (1999) · Psychopharmacology · doi:10.1007/s002130050964 · Cited by 95 · see citing works
Modelling brain diseases in mice: the challenges of design and analysis
Watase, K., & Zoghbi, H. Y. (2003) · Nature Reviews Genetics · doi:10.1038/nrg1045 · Cited by 94 · see citing works
Increased rates of cerebral glucose metabolism in a mouse model of fragile X mental retardation
Qin, M., Kang, J. Y., & Smith, C. B. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.242377399 · Cited by 93 · see citing works
Omission Learning after Instrumental Pretraining
Dickinson, A. (2010) · The Quarterly Journal of Experimental Psychology Section B · doi:10.1080/713932679 · Cited by 88 · see citing works
Fragile X syndrome at the turn of the century
Kooy, R. F., Willemsen, R., & Oostra, B. A. (2000) · Molecular Medicine Today · doi:10.1016/s1357-4310(00)01674-9 · Cited by 79 · see citing works
Abduljawad, K. A. J., Langley, R. W., Bradshaw, C. M., & Szabadi, E. (1998) · Journal of Psychopharmacology · doi:10.1177/026988119801200302 · Cited by 66 · see citing works
Abduljawad, K. A. J., Langley, R. W., Bradshaw, C. M., & Szabadi, E. (2001) · Journal of Psychopharmacology · doi:10.1177/026988110101500402 · Cited by 58 · see citing works
Swerdlow, N. R., Eastvold, A. D., Karban, B., Ploum, Y., Stephany, N., Geyer, M. A., Cadenhead, K. S., & Auerbach, P. P. (2002) · Psychopharmacology · doi:10.1007/s00213-002-1040-3 · Cited by 56 · see citing works
Impaired sensorimotor gating in patients with non-epileptic seizures
Pouretemad, H. R., Thompson, P. J., & Fenwick, P. B. C. (1998) · Epilepsy Research · doi:10.1016/s0920-1211(98)00014-x · Cited by 39 · see citing works
Graham, S. J., Langley, R. W., Bradshaw, C. M., & Szabadi, E. (2001) · Journal of Psychopharmacology · doi:10.1177/026988110101500411 · Cited by 38 · see citing works
Fragile X premutations and (TA)n estrogen receptor polymorphism in women with ovarian dysfunction
Syrrou, M., Georgiou, I. A., Patsalis, P. C., Bouba, I., Adonakis, G., & Pagoulatos, G. N. (1999) · American Journal of Medical Genetics · doi:10.1002/(sici)1096-8628(19990528)84:3 · Cited by 33 · see citing works
Midazolam effects on prepulse inhibition of the acoustic blink reflex
Schächinger, H., Müller, B. U., Strobel, W. M., Langewitz, W. A., & Ritz, R. (1999) · British Journal of Clinical Pharmacology · doi:10.1046/j.1365-2125.1999.00896.x · Cited by 32 · see citing works
Carvalho, O. M., Silva, A. J., & Balleine, B. W. (2001) · International Journal of Comparative Psychology · doi:10.46867/c4d01m · Cited by 18 · see citing works
Self-citationMiller (1999) · doi:10.1002/(sici)1096-8628(19990402)83:4
Turner (1996) · doi:10.1002/(sici)1096-8628(19960712)64:1
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- Authors
- Frankland, P. W., Wang, Y., Rosner, B., Shimizu, T., Balleine, B. W., Dykens, E. M., Ornitz, E. M., & Silva, A. J.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Ornitz, E M
- Silva, A J
- Venue
- Molecular Psychiatry
- Published
- 2004-02-10
- Volume
- 9
- Issue
- 4
- Pages
- 417-425
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- OpenAlex
- W2046570248
- Cited by
- 275
- References
- 42
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 2 · 2023: 11 · 2022: 14 · 2021: 12 · 2020: 12 · 2019: 14 · 2018: 12 · 2017: 16 · 2016: 10 · 2015: 15 · 2014: 22 · 2013: 13 · 2012: 18
- FWCI
- 4.80
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- 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
- fragile X syndrome, FMR1 gene, sensorimotor gating, prepulse inhibition, Fmr1 knockout mice, intellectual disability, attention deficits, autism spectrum disorder, adaptive behavior, learning deficits, compensatory mechanisms, human-mouse comparison
- MeSH terms
- Acoustic Stimulation, Adolescent, Analysis of Variance, Animals, Mental Disorders, Child, Child Behavior Disorders, Child Development Disorders, Pervasive, Cognition Disorders, Conditioning, Psychological, Disease Models, Animal, Fragile X Syndrome, Humans, Male, Mutation, Nerve Tissue Proteins, Neural Inhibition, Neuropsychological Tests, Predictive Value of Tests, Severity of Illness Index, Reflex, Startle, Ion Channel Gating, RNA-Binding Proteins, Mice, Knockout, Mice, Fragile X Messenger Ribonucleoprotein 1
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