Downregulation of Tonic GABAergic Inhibition in a Mouse Model of Fragile X Syndrome
Open accessAbstract
The absence of fragile X mental retardation protein results in the fragile X syndrome (FXS), a common form of mental retardation associated with attention deficit, autistic behavior, and epileptic seizures. The phenotype of FXS is reproduced in fragile X mental retardation 1 (fmr1) knockout (KO) mice that have region-specific altered expression of some gamma-aminobutyric acid (GABA(A)) receptor subunits. However, little is known about the characteristics of GABAergic inhibition in the subiculum of these animals. We employed patch-clamp recordings from subicular pyramidal cells in an in vitro slice preparation. In addition, semiquantitative polymerase chain reaction and western blot experiments were performed on subiculum obtained from wild-type (WT) and KO mice. We found that tonic GABA(A) currents were downregulated in fmr1 KO compared with WT neurons, whereas no significant differences were observed in phasic GABA(A) currents. Molecular biology analysis revealed that the tonic GABA(A) receptor subunits alpha5 and delta were underexpressed in the fmr1 KO mouse subiculum compared with WT. Because the subiculum plays a role in both cognitive functions and epileptic disorders, we propose that altered tonic inhibition in this structure contributes to the behavioral deficits and epileptic activity seen in FXS patients. This conclusion is in line with evidence implicating tonic GABA(A) inhibition in learning and memory.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
FMRP activity is regulated in response to metabotropic glutamate receptors, AMPA receptors, GABA receptors, NMDA receptors, and TrkB receptors.
“FMRP activity is regulated in response to metabotropic glutamate receptors (mGluRs) (78), 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid (AMPA) receptors (79), γ-aminobutyric acid (GABA) receptors (76,80,81), N-methyl-d-aspartate (NMDA) receptors (82)(83)(84), and the tyrosine kinase or BDNF/NT-3 growth factor (TrkB) receptors (85).”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [80]
The GABA receptor system is downregulated in fragile X syndrome, partially due to destabilization of mRNAs encoding GABA receptor subunits.
“The GABA receptor system has also been reported as downregulated in FXS, partially due to destabilization of the mRNAs encoding the GABA receptor subunits (76,80,113).”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [80]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
A new mathematical model for relative quantification in real-time RT-PCR
Pfaffl, M. W. (2001) · Nucleic Acids Research · doi:10.1093/nar/29.9.e45 · Cited by 34,610 · see citing works
Guideline to reference gene selection for quantitative real-time PCR
Radonić, A., Thulke, S., Mackay, I. M., Landt, O., Siegert, W., & Nitsche, A. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2003.11.177 · Cited by 1,645 · see citing works
The mGluR theory of fragile X mental retardation
Bear, M. F., Huber, K. M., & Warren, S. T. (2004) · Trends in Neurosciences · doi:10.1016/j.tins.2004.04.009 · Cited by 1,580 · see citing works
Altered synaptic plasticity in a mouse model of fragile X mental retardation
Huber, K. M., Gallagher, S. M., Warren, S. T., & Bear, M. F. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.122205699 · Cited by 1,349 · see citing works
Fritschy, J., & Mohler, H. (1995) · Journal of Comparative Neurology · doi:10.1002/cne.903590111 · Cited by 1,244 · 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
On the Origin of Interictal Activity in Human Temporal Lobe Epilepsy in Vitro
Cohen, I., Navarro, V., Clémenceau, S., Baulac, M., & Miles, R. (2002) · Science · doi:10.1126/science.1076510 · Cited by 1,001 · see citing works
Caraiscos, V. B., Elliott, E. M., You-Ten, K. E., Cheng, V., Belelli, D., Newell, J. G., Jackson, M. F., Lambert, J. J., Rosahl, T. W., Wafford, K. A., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0307231101 · Cited by 571 · see citing works
Separate Neural Bases of Two Fundamental Memory Processes in the Human Medial Temporal Lobe
Gabrieli, J. D. E., Brewer, J. B., Desmond, J. E., & Glover, G. H. (1997) · Science · doi:10.1126/science.276.5310.264 · Cited by 569 · see citing works
(1994) · PubMed · Cited by 565 · see citing works
RNA cargoes associating with FMRP reveal deficits in cellular functioning in Fmr1 null mice
Miyashiro, K. Y., Beckel-Mitchener, A., Purk, T. P., Becker, K. G., Barret, T., Liu, L., Carbonetto, S., Weiler, I. J., Greenough, W. T., & Eberwine, J. (2003) · Neuron · doi:10.1016/s0896-6273(03)00034-5 · Cited by 495 · see citing works
DeLorey, T. M., Handforth, A., Anagnostaras, S., Homanics, G. E., Minassian, B. A., Asatourian, A., Fanselow, M. S., Delgado‐Escueta, A. V., Ellison, G., & Olsen, R. W. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-20-08505.1998 · Cited by 459 · see citing works
Which GABA <sub>A</sub> Receptor Subunits Are Necessary for Tonic Inhibition in the Hippocampus?
Glykys, J., Mann, E. O., & Mody, I. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.4751-07.2008 · Cited by 370 · see citing works
Antar, L. N., Afroz, R., Dictenberg, J. B., Carroll, R. C., & Bassell, G. J. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.0099-04.2004 · Cited by 360 · see citing works
Spatial correlates of firing patterns of single cells in the subiculum of the freely moving rat
Sharp, P., & Green, C. (1994) · Journal of Neuroscience · doi:10.1523/jneurosci.14-04-02339.1994 · Cited by 348 · see citing works
GABAA receptor subunits in the rat hippocampus I: Immunocytochemical distribution of 13 subunits
Sperk, G., Schwarzer, C., Tsunashima, K., Fuchs, K., & Sieghart, W. (1997) · Neuroscience · doi:10.1016/s0306-4522(97)00146-2 · Cited by 336 · see citing works
Peng, Z., Huang, C., Stell, B. M., Módy, I., & Houser, C. R. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.2877-04.2004 · Cited by 321 · see citing works
Decreased expression of the GABAA receptor in fragile X syndrome
D'Hulst, C., De Geest, N., Reeve, S. P., Van Dam, D., De Deyn, P. P., Hassan, B. A., & Kooy, R. F. (2006) · Brain Research · doi:10.1016/j.brainres.2006.08.115 · Cited by 318 · see citing works
Todd, P. K., Mack, K. J., & Malter, J. S. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2336265100 · Cited by 280 · see citing works
Li, J., Pelletier, M. R., Perez-Velazquez, J. L., & Carlen, P. L. (2002) · Molecular and Cellular Neuroscience · doi:10.1006/mcne.2001.1085 · Cited by 268 · see citing works
Deficits in trace fear memory and long-term potentiation in a mouse model for fragile X syndrome
Zhao, M.-G., Toyoda, H., Ko, S. W., Ding, H.-K., Wu, L.-J., & Zhuo, M. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.1520-05.2005 · Cited by 258 · see citing works
Multiple and Plastic Receptors Mediate Tonic GABAAReceptor Currents in the Hippocampus
Scimemi, A., Semyanov, A. V., Sperk, G., Kullmann, D. M., & Walker, M. C. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.2520-05.2005 · Cited by 231 · see citing works
Zhang, N.-H., Wei, W.-Z., Mody, I., & Houser, C. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.1555-07.2007 · Cited by 221 · see citing works
Glykys, J. C., & Módy, I. (2006) · Journal of Neurophysiology · doi:10.1152/jn.01122.2005 · Cited by 216 · see citing works
Pavlidis, P., Ramaswami, M., & Tanouye, M. A. (1994) · Cell · doi:10.1016/0092-8674(94)90397-2 · Cited by 214 · see citing works
Decreased GABAA receptor expression in the seizure-prone fragile X mouse
Idrissi, A. E., Ding, X., Scalia, J., Trenkner, E., Brown, W. T., & Dobkin, C. (2004) · Neuroscience Letters · doi:10.1016/j.neulet.2004.11.087 · Cited by 210 · see citing works
Mertens, S., Benke, D., & Möhler, H. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)53413-x · Cited by 176 · see citing works
Atack, J. R., Bayley, P. J., Seabrook, G. R., Wafford, K. A., McKernan, R. M., & Dawson, G. R. (2006) · Neuropharmacology · doi:10.1016/j.neuropharm.2006.04.018 · Cited by 175 · see citing works
Abnormal Striatal GABA Transmission in the Mouse Model for the Fragile X Syndrome
Centonze, D., Rossi, S., Mercaldo, V., Napoli, I., Ciotti, M. T., De Chiara, V., Musella, A., Prosperetti, C., Calabresi, P., Bernardi, G., et al. (2008) · Biological Psychiatry · doi:10.1016/j.biopsych.2007.09.008 · Cited by 171 · see citing works
Gantois, I., Vandesompele, J., Speleman, F., Reyniers, E., D’Hooge, R., Severijnen, L.-A. W. F. M., Willemsen, R., Tassone, F., & Kooy, R. F. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2005.07.017 · Cited by 166 · see citing works
The GABAA receptor: a novel target for treatment of fragile X?
D’Hulst, C., & Kooy, R. F. (2007) · Trends in Neurosciences · doi:10.1016/j.tins.2007.06.003 · Cited by 166 · see citing works
Shen, H., Gong, Q. H., Yuan, M., & Smith, S. S. (2005) · Neuropharmacology · doi:10.1016/j.neuropharm.2005.04.026 · Cited by 160 · see citing works
Aschrafi, A., Cunningham, B. A., Edelman, G. M., & Vanderklish, P. W. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0409803102 · Cited by 148 · see citing works
Of mice and the fragile X syndrome
Kooy, R. F. (2003) · Trends in Genetics · doi:10.1016/s0168-9525(03)00017-9 · Cited by 134 · see citing works
Behavior and Physiology of Mice Lacking the GABA A ‐Receptor δ Subunit
Spigelman, I., Li, Z., Banerjee, P., Mihalek, R., Homanics, G. E., & Olsen, R. W. (2002) · Epilepsia · doi:10.1046/j.1528-1157.43.s.5.8.x · Cited by 120 · see citing works
Antar, L. N., & Bassell, G. J. (2003) · Neuron · doi:10.1016/s0896-6273(03)00090-4 · Cited by 117 · see citing works
Nishimura, T., Schwarzer, C., Gasser, E., Kato, N., Vezzani, A., & Sperk, G. (2005) · Neuroscience · doi:10.1016/j.neuroscience.2005.04.013 · Cited by 96 · see citing works
Understanding fragile X syndrome: insights from animal models
Bakker, C. E., & Oostra, B. A. (2003) · Cytogenetic and Genome Research · doi:10.1159/000072845 · Cited by 87 · see citing works
Lucignani, G., Panzacchi, A., Bosio, L., Moresco, R. M., Ravasi, L., Coppa, I., Chiumello, G., Frey, K. A., Koeppe, R. A., & Fazio, F. (2004) · NeuroImage · doi:10.1016/j.neuroimage.2003.10.050 · Cited by 75 · see citing works
Windpassinger, C., Kroisel, P. M., Wagner, K., & Petek, E. (2002) · Gene · doi:10.1016/s0378-1119(02)00649-2 · Cited by 71 · see citing works
The Subiculum: A Potential Site of Ictogenesis in Human Temporal Lobe Epilepsy
Wozny, C., Knopp, A., Lehmann, T., Heinemann, U., & Behr, J. (2005) · Epilepsia · doi:10.1111/j.1528-1167.2005.01066.x · Cited by 65 · see citing works
Involvement of cholinergic and gabaergic systems in the fragile X knockout mice
D’Antuono, M., Merlo, D., & Avoli, M. (2003) · Neuroscience · doi:10.1016/s0306-4522(03)00103-9 · Cited by 64 · see citing works
Self-citationThe fragile X gene and its function
Oostra, B. A., & Chiurazzi, P. (2001) · Clinical Genetics · doi:10.1034/j.1399-0004.2001.600601.x · Cited by 52 · see citing works
Rat subicular networks gate hippocampal output activity in an in vitro model of limbic seizures
Benini, R., & Avoli, M. (2005) · The Journal of Physiology · doi:10.1113/jphysiol.2005.088708 · Cited by 48 · see citing works
Self-citationAberrant GABAAReceptor Expression in the Dentate Gyrus of the Epileptic Mutant Mouse Stargazer
Payne, H. L., Donoghue, P. S., Connelly, W. M., Hinterreiter, S., Tiwari, P., Ives, J. H., Hann, V., Sieghart, W., Lees, G., & Thompson, C. L. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.1088-06.2006 · Cited by 37 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Interneuron dysfunction in psychiatric disorders
Marín, O. (2012) · Nature Reviews Neuroscience · doi:10.1038/nrn3155 · Cited by 1,190 · see citing works
Fragile X Syndrome: Loss of Local mRNA Regulation Alters Synaptic Development and Function
Bassell, G. J., & Warren, S. T. (2008) · Neuron · doi:10.1016/j.neuron.2008.10.004 · Cited by 1,051 · see citing works
Hippocampal GABAergic Inhibitory Interneurons
Pelkey, K. A., Chittajallu, R., Craig, M. T., Tricoire, L., Wester, J. C., & McBain, C. J. (2017) · Physiological Reviews · doi:10.1152/physrev.00007.2017 · Cited by 889 · see citing works
Hagerman, R. J., Berry-Kravis, E., Hazlett, H. C., Bailey, D. B., Moine, H., Kooy, R. F., Tassone, F., Gantois, I., Sonenberg, N., Mandel, J. L., et al. (2017) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2017.65 · Cited by 838 · see citing works
Excitation/Inhibition Imbalance in Animal Models of Autism Spectrum Disorders
Lee, E., Lee, J., & Kim, E. (2017) · Biological Psychiatry · doi:10.1016/j.biopsych.2016.05.011 · Cited by 468 · see citing works
Extrasynaptic GABA <sub>A</sub> Receptors: Form, Pharmacology, and Function
Belelli, D., Harrison, N. L., Maguire, J., Macdonald, R. L., Walker, M. C., & Cope, D. W. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.3340-09.2009 · Cited by 464 · see citing works
“Last, aberrant tonic inhibition has been implicated in multiple pathophysiological conditions, including fragile X mental retardation (Curia et al., 2009), -hydroxybutyric acid (GHB)uria (Drasbek et al., 2008), stress (Maguire and Mody, 2007), disorders associated with the menstrual cycle and…”
BackgroundFragile X syndrome: causes, diagnosis, mechanisms, and therapeutics
Bagni, C., Tassone, F., Neri, G., & Hagerman, R. (2012) · Journal of Clinical Investigation · doi:10.1172/jci63141 · Cited by 321 · see citing works
Olmos-Serrano, J. L., Paluszkiewicz, S. M., Martin, B. S., Kaufmann, W. E., Corbin, J. G., & Huntsman, M. M. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.1714-10.2010 · Cited by 309 · see citing works
Circuit level defects in the developing neocortex of fragile X mice
Gonçalves, J. T., Anstey, J. E., Golshani, P., & Portera-Cailliau, C. (2013) · Nature Neuroscience · doi:10.1038/nn.3415 · Cited by 279 · see citing works
Fragile X and autism: intertwined at the molecular level leading to targeted treatments
Hagerman, R., Hoem, G., & Hagerman, P. (2010) · Molecular Autism · doi:10.1186/2040-2392-1-12 · Cited by 247 · see citing works
Lee, V., & Maguire, J. (2014) · Frontiers in Neural Circuits · doi:10.3389/fncir.2014.00003 · Cited by 228 · see citing works
Deidda, G., Bozarth, I. F., & Cancedda, L. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00119 · Cited by 192 · see citing works
Early developmental alterations in GABAergic protein expression in fragile X knockout mice
Adusei, D. C., Pacey, L. K. K., Chen, D., & Hampson, D. R. (2010) · Neuropharmacology · doi:10.1016/j.neuropharm.2010.05.002 · Cited by 139 · see citing works
Pacey, L. K. K., Heximer, S. P., & Hampson, D. R. (2009) · Molecular Pharmacology · doi:10.1124/mol.109.056127 · Cited by 133 · see citing works
Lazaro, M. T., Taxidis, J., Shuman, T., Bachmutsky, I., Ikrar, T., Santos, R., Marcello, G. M., Mylavarapu, A., Chandra, S., Foreman, A., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.05.006 · Cited by 125 · see citing works
Prenatal stress and inhibitory neuron systems: implications for neuropsychiatric disorders
Fine, R., Zhang, J., & Stevens, H. E. (2014) · Molecular Psychiatry · doi:10.1038/mp.2014.35 · Cited by 96 · see citing works
Garcia-Pino, E., Gessele, N., & Koch, U. (2017) · The Journal of Neuroscience · doi:10.1523/jneurosci.2310-16.2017 · Cited by 58 · see citing works
Hyperexcitability and homeostasis in fragile X Syndrome.
Liu, X., Kumar, V., Tsai, N.-P., & Auerbach, B. D. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.805929 · Cited by 53 · see citing works
De Rubeis, S., Fernández, E., Buzzi, A., Di Marino, D., & Bagni, C. (2012) · Advances in Experimental Medicine and Biology · doi:10.1007/978-3-7091-0932-8_23 · Cited by 48 · see citing works
The neurochemical basis for the treatment of autism spectrum disorders and Fragile X syndrome
Hampson, D. R., Adusei, D. C., & Pacey, L. K. K. (2011) · Biochemical Pharmacology · doi:10.1016/j.bcp.2011.02.005 · Cited by 34 · see citing works
- Authors
- Curia, G., Papouin, T., Séguéla, P., & Avoli, M.
- Affiliations
- Montreal Neurological Institute and Hospital (CA)
- Venue
- Cerebral Cortex
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-09-11
- Volume
- 19
- Issue
- 7
- Pages
- 1515-1520
- ISSN
- 1047-3211 (ISSN-L)
- 1460-2199
- PMC
- PMC4873279
- OpenAlex
- W2109792092
- Cited by
- 218
- References
- 45
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 1 · 2023: 6 · 2022: 9 · 2021: 8 · 2020: 15 · 2019: 9 · 2018: 10 · 2017: 17 · 2016: 8 · 2015: 14 · 2014: 26 · 2013: 18 · 2012: 19
- FWCI
- 9.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cerebral Cortex (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Funders
- Canadian Institutes of Health Research (8109_5, 8109_4)
- 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, Fmr1 knockout mice, GABAA receptor subunits, alpha5 subunit, delta subunit, subiculum, epilepsy, learning and memory
- MeSH terms
- Animals, Disease Models, Animal, Fragile X Syndrome, gamma-Aminobutyric Acid, Humans, Male, Mice, Inbred C57BL, Neural Inhibition, Synaptic Transmission, Receptors, GABA-A, Down-Regulation, Mice, Knockout, Mice, Fragile X Messenger Ribonucleoprotein 1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
