Major defects in neocortical GABAergic inhibitory circuits in mice lacking the fragile X mental retardation protein
Open accessAbstract
This study focused on the cytoarchitectonic and morphological differences in GABA-releasing interneurons between adult Fmr1 knock-out (FMR1KO) and wild-type (WT) mice in the somatosensory cortex. Our results showed a robust reorganization of neocortical, but not hippocampal inhibitory circuits in the FMR1KO mouse. The reorganization is characterized by a significant reduction (20%, p<0.001) in the densities of parvalbumin (PV)-positive, but not calbindin (CB) and calretinin (CR)-positive interneurons. A significant enlargement of soma size and an altered lamina distribution of PV but not CR and CB cells was also observed. Additionally, there was a modest but significant increase in TrkB-immunoreactivity in PV-positive cells in the FMR1KO mouse. These results provide the first report showing significant alterations of GABA-releasing interneurons in the mouse model of fragile X syndrome. Uncovering the changes in specific GABAergic inhibitory circuits could help understand mechanisms underlying the behavior deficits of fragile X syndrome and autism.
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?
In Fmr1 KO somatosensory cortex, PV neurons receive reduced excitatory drive, causing reduced network inhibition and increased UP states (Selby et al., 2007; Gibson et al., 2008).
“In the somatosensory cortex of Fmr1 KO mice, PV neurons receive reduced excitatory drive resulting in reduced inhibition in the network and increased UP states (Selby et al., 2007; Gibson et al., 2008).”
From Matrix metalloproteinase-9 deletion rescues auditory evoked potential habituation deficit in a mouse model of Fragile X Syndrome (2016) · cites this paper as Selby et al., 2007
High MMP-9 may reduce PNN formation around PV interneurons, affecting their activity (Cabungcal et al., 2013), leading to impaired inhibition (Selby et al., 2007; Gibson et al., 2008) and enhanced excitability in Fmr1 KO auditory cortex.
“High MMP-9 levels may result in reduced PNN formation around PV interneurons affecting their activity (Cabungcal et al., 2013) and leading to impaired inhibition (Selby et al., 2007; Gibson et al., 2008), and enhanced excitability in Fmr1 KO auditory cortex.”
From Matrix metalloproteinase-9 deletion rescues auditory evoked potential habituation deficit in a mouse model of Fragile X Syndrome (2016) · cites this paper as Selby et al., 2007
Canonical ASD mouse models were shown to display a reduction in the number of PV-immunoreactive cells in various brain regions.
“As already reported in several studies [47, 72–74] canonical ASD mouse models were shown to display a reduction in the number of PV-immunoreactive cells in various brain regions.”
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
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
Dendritic Spine Structural Anomalies in Fragile-X Mental Retardation Syndrome
Irwin, S. A. (2000) · Cerebral Cortex · doi:10.1093/cercor/10.10.1038 · Cited by 626 · see citing works
Analysis of neocortex in three males with the Fragile X syndrome
Hinton, V. J., Brown, W. T., Wisniewski, K., & Rudelli, R. D. (1991) · American Journal of Medical Genetics · doi:10.1002/ajmg.1320410306 · Cited by 527 · 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
Sensorimotor gating abnormalities in young males with fragile X syndrome and Fmr1-knockout mice.
Frankland, P. W., Wang, Y., Rosner, B., Shimizu, T., Balleine, B. W., Dykens, E. M., Ornitz, E. M., & Silva, A. J. (2004) · Molecular Psychiatry · doi:10.1038/sj.mp.4001432 · Cited by 275 · 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
Chuang, S.-C., Zhao, W., Bauchwitz, R., Yan, Q., Bianchi, R., & Wong, R. K. S. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.1777-05.2005 · Cited by 190 · see citing works
Local Protein Synthesis and Spine Morphogenesis: Fragile X Syndrome and Beyond
Grossman, A. W., Aldridge, G. M., Weiler, I. J., & Greenough, W. T. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.1790-06.2006 · Cited by 178 · see citing works
Major Effects of Sensory Experiences on the Neocortical Inhibitory Circuits
Jiao, Y., Zhang, C., Yanagawa, Y., & Sun, Q. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.2478-06.2006 · Cited by 168 · see citing works
Self-citationGantois, 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
Ren, J. Q., Aika, Y., Heizmann, C. W., & Kosaka, T. (1992) · Experimental Brain Research · doi:10.1007/bf00230378 · Cited by 148 · see citing works
Structural and Functional Aberrations in the Cerebral Cortex of Tenascin-C Deficient Mice
Irintchev, A., Rollenhagen, A., Troncoso, E., Kiss, J. Z., & Schachner, M. (2005) · Cerebral Cortex · doi:10.1093/cercor/bhh195 · Cited by 137 · see citing works
Disruption of Interneuron Development
Levitt, P. R. (2005) · Epilepsia · doi:10.1111/j.1528-1167.2005.00305.x · Cited by 128 · see citing works
Galvez, R., Gopal, A. R., & Greenough, W. T. (2003) · Brain Research · doi:10.1016/s0006-8993(03)02363-1 · Cited by 118 · see citing works
BDNF Regulates the Expression of Fragile X Mental Retardation Protein mRNA in the Hippocampus
Castrén, M. L., Lampinen, K. E., Miettinen, R. A., Koponen, E., Sipola, I., Bakker, C. E., Oostra, B. A., & Ċastrén, E. (2002) · Neurobiology of Disease · doi:10.1006/nbdi.2002.0544 · Cited by 47 · see citing works
Miller (1999) · doi:10.1002/(sici)1096-8628(19990402)83:4
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
Common circuit defect of excitatory-inhibitory balance in mouse models of autism
Gogolla, N., LeBlanc, J. J., Quast, K. B., Südhof, T. C., Fagiolini, M., & Hensch, T. K. (2009) · Journal of Neurodevelopmental Disorders · doi:10.1007/s11689-009-9023-x · Cited by 610 · see citing works
Gao, R., & Penzes, P. (2015) · Current Molecular Medicine · doi:10.2174/1566524015666150303003028 · Cited by 516 · see citing works
“Furthermore, knockout mice have significant reductions and drastic lamina redistributions of PV+ interneurons in the neocortex, but not hippocampus, suggesting these effects may involve region-specific gamma oscillation deficiencies [246].”
BackgroundExcitation/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
GABAergic interneuron origin of schizophrenia pathophysiology
Nakazawa, K., Zsiros, V., Jiang, Z., Nakao, K., Kolata, S., Zhang, S., & Belforte, J. E. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.01.022 · Cited by 498 · see citing works
Antoine, M. W., Langberg, T., Schnepel, P., & Feldman, D. E. (2019) · Neuron · doi:10.1016/j.neuron.2018.12.026 · Cited by 413 · see citing works
Exogenous and evoked oxytocin restores social behavior in the <i>Cntnap2</i> mouse model of autism
Peñagarikano, O., Lázaro, M. T., Lu, X.-H., Gordon, A., Dong, H., Lam, H. A., Peles, E., Maidment, N. T., Murphy, N. P., Yang, X. W., et al. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.3010257 · Cited by 378 · see citing works
Altered neural connectivity in excitatory and inhibitory cortical circuits in autism
Zikopoulos, B., & Barbas, H. (2013) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2013.00609 · Cited by 313 · see citing works
Hashemi, E., Ariza, J., Rogers, H., Noctor, S. C., & Martínez-Cerdeño, V. (2016) · Cerebral Cortex · doi:10.1093/cercor/bhw021 · Cited by 322 · see citing works
Reversing behavioural abnormalities in mice exposed to maternal inflammation
Shin Yim, Y., Park, A., Berrios, J., Lafourcade, M., Pascual, L. M., Soares, N., Yeon Kim, J., Kim, S., Kim, H., Waisman, A., et al. (2017) · Nature · doi:10.1038/nature23909 · Cited by 303 · 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
IL-17a promotes sociability in mouse models of neurodevelopmental disorders
Reed, M. D., Yim, Y. S., Wimmer, R. D., Kim, H., Ryu, C., Welch, G. M., Andina, M., King, H. O., Waisman, A., Halassa, M. M., et al. (2020) · Nature · doi:10.1038/s41586-019-1843-6 · Cited by 274 · see citing works
The Emerging Picture of Autism Spectrum Disorder: Genetics and Pathology
Chen, J. A., Peñagarikano, O., Belgard, T. G., Swarup, V., & Geschwind, D. H. (2015) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-012414-040405 · Cited by 254 · see citing works
Filice, F., Vörckel, K. J., Sungur, A. Ö., Wöhr, M., & Schwaller, B. (2016) · Molecular Brain · doi:10.1186/s13041-016-0192-8 · Cited by 240 · see citing works
Wöhr, M., Orduz, D., Gregory, P., Moreno, H., Khan, U., Vörckel, K. J., Wolfer, D. P., Welzl, H., Gall, D., Schiffmann, S. N., et al. (2015) · Translational Psychiatry · doi:10.1038/tp.2015.19 · Cited by 258 · 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
Henderson, C., Wijetunge, L., Kinoshita, M. N., Shumway, M., Hammond, R. S., Postma, F. R., Brynczka, C., Rush, R., Thomas, A., Paylor, R., et al. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3004218 · Cited by 249 · see citing works
Cortical interneuron development: a tale of time and space
Hu, J. S., Vogt, D., Sandberg, M., & Rubenstein, J. L. (2017) · Development · doi:10.1242/dev.132852 · Cited by 189 · 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
Circuit and Plasticity Defects in the Developing Somatosensory Cortex of<i>Fmr1</i>Knock-Out Mice
Bureau, I., Shepherd, G. M. G., & Svoboda, K. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.1076-08.2008 · Cited by 201 · see citing works
Sinclair, D., Oranje, B., Razak, K. A., Siegel, S. J., & Schmid, S. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.05.029 · Cited by 198 · see citing works
“The deficit in early sensory processing will also allow an examination of circuit and cellular deficits (Gibson et al., 2008; Hays et al., 2011; Selby et al., 2007) that may be more tractable than complex social behaviors and importantly conserved across species.”
Translation-relevant EEG phenotypes in a mouse model of Fragile X Syndrome.
Lovelace, J. W., Ethell, I. M., Binder, D. K., & Razak, K. A. (2018) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.03.012 · Cited by 154 · see citing works
Wen, T. H., Afroz, S., Reinhard, S. M., Palacios, A. R., Tapia, K., Binder, D. K., Razak, K. A., & Ethell, I. M. (2018) · Cerebral Cortex · doi:10.1093/cercor/bhx258 · Cited by 165 · 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
Lovelace, J. W., Wen, T. H., Reinhard, S., Hsu, M. S., Sidhu, H., Ethell, I. M., Binder, D. K., & Razak, K. A. (2016) · Neurobiology of Disease · doi:10.1016/j.nbd.2016.02.002 · Cited by 115 · 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
Barnes, S. A., Pinto-Duarte, A., Kappe, A., Zembrzycki, A., Metzler, A., Mukamel, E. A., Lucero, J., Wang, X., Sejnowski, T. J., Markou, A., et al. (2015) · Molecular Psychiatry · doi:10.1038/mp.2015.113 · Cited by 92 · see citing works
Greco, C. M., Navarro, C. S., Hunsaker, M. R., Maezawa, I., Shuler, J. F., Tassone, F., Delany, M., Au, J. W., Berman, R. F., Jin, L.-W., et al. (2011) · Molecular Autism · doi:10.1186/2040-2392-2-2 · Cited by 90 · see citing works
Aberrant differentiation of glutamatergic cells in neocortex of mouse model for fragile X syndrome.
Tervonen, T. A., Louhivuori, V., Sun, X., Hokkanen, M.-E., Kratochwil, C. F., Zebryk, P., Castrén, E., & Castrén, M. L. (2009) · Neurobiology of Disease · doi:10.1016/j.nbd.2008.10.010 · Cited by 82 · see citing works
Nomura, T., Musial, T. F., Marshall, J. J., Zhu, Y., Remmers, C. L., Xu, J., Nicholson, D. A., & Contractor, A. (2017) · The Journal of Neuroscience · doi:10.1523/jneurosci.2893-16.2017 · Cited by 64 · 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
Siegel, J. J., Chitwood, R. A., Ding, J. M., Payne, C., Taylor, W., Gray, R., Zemelman, B. V., & Johnston, D. (2017) · The Journal of Neuroscience · doi:10.1523/jneurosci.0571-17.2017 · Cited by 27 · see citing works
New therapeutic options for autism spectrum disorder: experimental evidences
Peñagarikano, O. (2015) · Experimental Neurobiology · doi:10.5607/en.2015.24.4.301 · Cited by 24 · see citing works
- Authors
- Selby, L., Zhang, C., & Sun, Q.-Q.
- Affiliations
- University of Wyoming (US)
- Corresponding author
- Sun, Qian-Quan
- ORCID
- Sun, Qian-Quan
- Venue
- Neuroscience Letters
- Publisher
- Elsevier BV
- Published
- 2007-02
- Volume
- 412
- Issue
- 3
- Pages
- 227-232
- ISSN
- 0304-3940 (ISSN-L)
- PMC
- PMC1839948
- OpenAlex
- W2172294620
- Cited by
- 245
- References
- 16
- Citations by year
- 2026: 12 · 2025: 6 · 2024: 9 · 2023: 14 · 2022: 16 · 2021: 14 · 2020: 15 · 2019: 15 · 2018: 9 · 2017: 18 · 2016: 14 · 2015: 17 · 2014: 13 · 2013: 8 · 2012: 15
- FWCI
- 3.99
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neuroscience Letters (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Wyoming
- National Institutes of Health (2p20rr016474-09)
- National Institute of Neurological Disorders and Stroke (R01NS057415)
- National Center for Research Resources (P20- RR-16474-04, P20-RR-016474, P20RR015640)
- Office of Experimental Program to Stimulate Competitive Research
- 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
- fragile X syndrome, Fmr1 knockout mice, GABAergic interneurons, somatosensory cortex, parvalbumin interneurons, calbindin, calretinin, TrkB, autism spectrum disorder
- MeSH terms
- Animals, Cell Count, gamma-Aminobutyric Acid, Interneurons, Mice, Inbred C57BL, Nerve Net, Neural Inhibition, Parvalbumins, Gene Expression, Mice, Knockout, Neocortex, Receptor, trkB, Mice, Fragile X Mental Retardation Protein, 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
