Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Channelopathies in fragile X syndrome

Nature Reviews Neuroscience volume 22, pages 275–289 (2021)Cite this article

Subjects

Abstract

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and the leading monogenic cause of autism. The condition stems from loss of fragile X mental retardation protein (FMRP), which regulates a wide range of ion channels via translational control, protein–protein interactions and second messenger pathways. Rapidly increasing evidence demonstrates that loss of FMRP leads to numerous ion channel dysfunctions (that is, channelopathies), which in turn contribute significantly to FXS pathophysiology. Consistent with this, pharmacological or genetic interventions that target dysregulated ion channels effectively restore neuronal excitability, synaptic function and behavioural phenotypes in FXS animal models. Recent studies further support a role for direct and rapid FMRP–channel interactions in regulating ion channel function. This Review lays out the current state of knowledge in the field regarding channelopathies and the pathogenesis of FXS, including promising therapeutic implications.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Overview of channelopathies in FXS.
Fig. 2: FMRP controls ion channel functions through multiple mechanisms.

Similar content being viewed by others

References

  1. Penagarikano, O., Mulle, J. G. & Warren, S. T. The pathophysiology of fragile X syndrome. Annu. Rev. Genomics Hum. Genet. 8, 109–129 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Sitzmann, A. F., Hagelstrom, R. T., Tassone, F., Hagerman, R. J. & Butler, M. G. Rare FMR1 gene mutations causing fragile X syndrome: a review. Am. J. Med. Genet. A 176, 11–18 (2018).

    Article  CAS  PubMed  Google Scholar 

  3. Contractor, A., Klyachko, V. A. & Portera-Cailliau, C. Altered neuronal circuit excitability fragile X syndrome. Neuron 87, 699–715 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Devys, D., Lutz, Y., Rouyer, N., Bellocq, J. P. & Mandel, J. L. The FMR-1 protein is cytoplasmic, most abundant in neurons and appears normal in carriers of a fragile X premutation. Nat. Genet. 4, 335–340 (1993).

    Article  CAS  PubMed  Google Scholar 

  5. Brager, D. H. & Johnston, D. Channelopathies and dendritic dysfunction in fragile X syndrome. Brain Res. Bull. 103, 11–17 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ferron, L. Fragile X mental retardation protein controls ion channel expression and activity. J. Physiol. 594, 5861–5867 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Salcedo-Arellano, M. J., Hagerman, R. J. & Martinez-Cerdeno, V. Fragile X syndrome: clinical presentation, pathology and treatment. Gac. Med. Mex. 156, 60–66 (2020).

    PubMed  Google Scholar 

  8. Nelson, S. B. & Valakh, V. Excitatory/inhibitory balance and circuit homeostasis in autism spectrum disorders. Neuron 87, 684–698 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Morin-Parent, F., Champigny, C., Lacroix, A., Corbin, F. & Lepage, J. F. Hyperexcitability and impaired intracortical inhibition in patients with fragile-X syndrome. Transl Psychiatry 9, 312 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Berry-Kravis, E. Epilepsy in fragile X syndrome. Dev. Med. Child Neurol. 44, 724–728 (2002).

    Article  PubMed  Google Scholar 

  11. Sabaratnam, M., Vroegop, P. G. & Gangadharan, S. K. Epilepsy and EEG findings in 18 males with fragile X syndrome. Seizure 10, 60–63 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Miller, L. J. et al. Electrodermal responses to sensory stimuli in individuals with fragile X syndrome: a preliminary report. Am. J. Med. Genet. 83, 268–279 (1999).

    Article  CAS  PubMed  Google Scholar 

  13. Merenstein, S. A. et al. Molecular–clinical correlations in males with an expanded FMR1 mutation. Am. J. Med. Genet. 64, 388–394 (1996).

    Article  CAS  PubMed  Google Scholar 

  14. Kronk, R. et al. Prevalence, nature, and correlates of sleep problems among children with fragile X syndrome based on a large scale parent survey. Sleep 33, 679–687 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Carotenuto, M. et al. Polysomnographic findings in fragile X syndrome children with EEG abnormalities. Behav. Neurol. 2019, 5202808 (2019).

    PubMed  PubMed Central  Google Scholar 

  16. Scharf, S. S., Gasparini, F., Spooren, W. & Lindemann, L. in Fragile X Syndrome: From Genetics to Targeted Treatment (eds Willemsen, R. & Kooy, R. F.) 363–399 (Elsevier, 2017).

  17. Chen, L. & Toth, M. Fragile X mice develop sensory hyperreactivity to auditory stimuli. Neuroscience 103, 1043–1050 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Musumeci, S. A. et al. Audiogenic seizures susceptibility in transgenic mice with fragile X syndrome. Epilepsia 41, 19–23 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. Yan, Q. J., Rammal, M., Tranfaglia, M. & Bauchwitz, R. P. Suppression of two major fragile X syndrome mouse model phenotypes by the mGluR5 antagonist MPEP. Neuropharmacology 49, 1053–1066 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Osterweil, E. K. et al. Lovastatin corrects excess protein synthesis and prevents epileptogenesis in a mouse model of fragile X syndrome. Neuron 77, 243–250 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Curia, G., Gualtieri, F., Bartolomeo, R., Vezzali, R. & Biagini, G. Resilience to audiogenic seizures is associated with p-ERK1/2 dephosphorylation in the subiculum of Fmr1 knockout mice. Front. Cell Neurosci. 7, 46 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gross, C. et al. Selective role of the catalytic PI3K subunit p110β in impaired higher order cognition in fragile X syndrome. Cell Rep. 11, 681–688 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Busquets-Garcia, A. et al. Targeting the endocannabinoid system in the treatment of fragile X syndrome. Nat. Med. 19, 603–607 (2013).

    Article  CAS  PubMed  Google Scholar 

  24. Rotschafer, S. & Razak, K. Altered auditory processing in a mouse model of fragile X syndrome. Brain Res. 1506, 12–24 (2013).

    Article  CAS  PubMed  Google Scholar 

  25. He, C. X. et al. Tactile defensiveness and impaired adaptation of neuronal activity in the Fmr1 knock-out mouse model of autism. J. Neurosci. 37, 6475–6487 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Frankland, P. W. et al. Sensorimotor gating abnormalities in young males with fragile X syndrome and Fmr1-knockout mice. Mol. Psychiatry 9, 417–425 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Dansie, L. E. et al. Long-lasting effects of minocycline on behavior in young but not adult fragile X mice. Neuroscience 246, 186–198 (2013).

    Article  CAS  PubMed  Google Scholar 

  28. Oddi, D. et al. Early social enrichment rescues adult behavioral and brain abnormalities in a mouse model of fragile X syndrome. Neuropsychopharmacology 40, 1113–1122 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Heulens, I., D’Hulst, C., Van Dam, D., De Deyn, P. P. & Kooy, R. F. Pharmacological treatment of fragile X syndrome with GABAergic drugs in a knockout mouse model. Behav. Brain Res. 229, 244–249 (2012).

    Article  CAS  PubMed  Google Scholar 

  30. Heard, T. T. et al. EEG abnormalities and seizures in genetically diagnosed fragile X syndrome. Int. J. Dev. Neurosci. 38, 155–160 (2014).

    Article  PubMed  Google Scholar 

  31. Knoth, I. S., Vannasing, P., Major, P., Michaud, J. L. & Lippe, S. Alterations of visual and auditory evoked potentials in fragile X syndrome. Int. J. Dev. Neurosci. 36, 90–97 (2014).

    Article  PubMed  Google Scholar 

  32. Castren, M., Paakkonen, A., Tarkka, I. M., Ryynanen, M. & Partanen, J. Augmentation of auditory N1 in children with fragile X syndrome. Brain Topogr. 15, 165–171 (2003).

    Article  PubMed  Google Scholar 

  33. Gibson, J. R., Bartley, A. F., Hays, S. A. & Huber, K. M. Imbalance of neocortical excitation and inhibition and altered UP states reflect network hyperexcitability in the mouse model of fragile X syndrome. J. Neurophysiol. 100, 2615–2626 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Hays, S. A., Huber, K. M. & Gibson, J. R. Altered neocortical rhythmic activity states in Fmr1 KO mice are due to enhanced mGluR5 signaling and involve changes in excitatory circuitry. J. Neurosci. 31, 14223–14234 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ronesi, J. A. et al. Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome. Nat. Neurosci. 15, 431–440, S1 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Goncalves, J. T., Anstey, J. E., Golshani, P. & Portera-Cailliau, C. Circuit level defects in the developing neocortex of fragile X mice. Nat. Neurosci. 16, 903–909 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Domanski, A. P. F., Booker, S. A., Wyllie, D. J. A., Isaac, J. T. R. & Kind, P. C. Cellular and synaptic phenotypes lead to disrupted information processing in Fmr1-KO mouse layer 4 barrel cortex. Nat. Commun. 10, 4814 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Goel, A. et al. Impaired perceptual learning in a mouse model of fragile X syndrome is mediated by parvalbumin neuron dysfunction and is reversible. Nat. Neurosci. 21, 1404–1411 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Garcia-Pino, E., Gessele, N. & Koch, U. Enhanced excitatory connectivity and disturbed sound processing in the auditory brainstem of fragile X mice. J. Neurosci. 37, 7403–7419 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. McCullagh, E. A., Salcedo, E., Huntsman, M. M. & Klug, A. Tonotopic alterations in inhibitory input to the medial nucleus of the trapezoid body in a mouse model of fragile X syndrome. J. Comp. Neurol. 525, 3543–3562 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Rotschafer, S. E., Marshak, S. & Cramer, K. S. Deletion of Fmr1 alters function and synaptic inputs in the auditory brainstem. PLoS ONE 10, e0117266 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Chuang, S. C. et al. Prolonged epileptiform discharges induced by altered group I metabotropic glutamate receptor-mediated synaptic responses in hippocampal slices of a fragile X mouse model. J. Neurosci. 25, 8048–8055 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Deng, P. Y. & Klyachko, V. A. Genetic upregulation of BK channel activity normalizes multiple synaptic and circuit defects in a mouse model of fragile X syndrome. J. Physiol. 594, 83–97 (2016).

    Article  CAS  PubMed  Google Scholar 

  44. Wahlstrom-Helgren, S. & Klyachko, V. A. GABAB receptor-mediated feed-forward circuit dysfunction in the mouse model of fragile X syndrome. J. Physiol. 593, 5009–5024 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wahlstrom-Helgren, S. & Klyachko, V. A. Dynamic balance of excitation and inhibition rapidly modulates spike probability and precision in feed-forward hippocampal circuits. J. Neurophysiol. 116, 2564–2575 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Martin, B. S., Corbin, J. G. & Huntsman, M. M. Deficient tonic GABAergic conductance and synaptic balance in the fragile X syndrome amygdala. J. Neurophysiol. 112, 890–902 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Martin, B. S. et al. Rescue of deficient amygdala tonic γ-aminobutyric acidergic currents in the Fmr–/y mouse model of fragile X syndrome by a novel γ-aminobutyric acid type A receptor-positive allosteric modulator. J. Neurosci. Res. 94, 568–578 (2016).

    Article  CAS  PubMed  Google Scholar 

  48. Olmos-Serrano, J. L. et al. Defective GABAergic neurotransmission and pharmacological rescue of neuronal hyperexcitability in the amygdala in a mouse model of fragile X syndrome. J. Neurosci. 30, 9929–9938 (2010). This study reveals inhibitory synapse abnormalities in the amygdala of an FXS mouse model,and provides evidence that pharmacological approaches targeting the GABAergic system may be a viable therapeutic approach to correct amygdala-dependent symptoms in FXS.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Vislay, R. L. et al. Homeostatic responses fail to correct defective amygdala inhibitory circuit maturation in fragile X syndrome. J. Neurosci. 33, 7548–7558 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Suvrathan, A., Hoeffer, C. A., Wong, H., Klann, E. & Chattarji, S. Characterization and reversal of synaptic defects in the amygdala in a mouse model of fragile X syndrome. Proc. Natl Acad. Sci. USA 107, 11591–11596 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Deng, P. Y. et al. Voltage-independent SK-channel dysfunction causes neuronal hyperexcitability in the hippocampus of Fmr1 knock-out mice. J. Neurosci. 39, 28–43 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Deng, P. Y. & Klyachko, V. A. Increased persistent sodium current causes neuronal hyperexcitability in the entorhinal cortex of Fmr1 knockout mice. Cell Rep. 16, 3157–3166 (2016). This study identifies Na+ channel dysregulation as a major cause of neuronal hyperexcitability in cortical FXS neurons and uncovers a mechanism via which increased mGluR5 signalling causes neuronal hyperexcitability in an FXS mouse model.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. El-Hassar, L. et al. Modulators of Kv3 potassium channels rescue the auditory function of fragile X Mice. J. Neurosci. 39, 4797–4813 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Routh, B. N. et al. Increased transient Na+ conductance and action potential output in layer 2/3 prefrontal cortex neurons of the fmr1–/y mouse. J. Physiol. 595, 4431–4448 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Meredith, R. M., Holmgren, C. D., Weidum, M., Burnashev, N. & Mansvelder, H. D. Increased threshold for spike-timing-dependent plasticity is caused by unreliable calcium signaling in mice lacking fragile X gene FMR1. Neuron 54, 627–638 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Brager, D. H., Akhavan, A. R. & Johnston, D. Impaired dendritic expression and plasticity of h-channels in the Fmr1–/y mouse model of fragile X syndrome. Cell Rep. 1, 225–233 (2012). This study reports elevated dendritic expression of HCN channels coupled with impaired h-channel plasticity, which may underlie some of the cognitive impairments associated with FXS.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Zhang, Y. et al. Dendritic channelopathies contribute to neocortical and sensory hyperexcitability in Fmr1–/y mice. Nat. Neurosci. 17, 1701–1709 (2014). This study reveals dysfunctions of HCN and BK channels within the dendritic compartment, and provides evidence that BK channel openers have potential to address the sensory hypersensitivity aspects of FXS.

    Article  CAS  PubMed  Google Scholar 

  58. Kalmbach, B. E., Johnston, D. & Brager, D. H. Cell-type specific channelopathies in the prefrontal cortex of the Fmr1–/y mouse model of fragile X syndrome. eNeuro 2, 0114–0115 (2015). This study shows cell type-specific alterations in A-type K+ channels and HCN channels in two types of neighbouring neurons in the prefrontal cortex of Fmr1 KO mice, which highlights the importance of understanding cell type-specific changes in neuronal excitability within the context of FXS.

    Article  Google Scholar 

  59. Booker, S. A. et al. Altered dendritic spine function and integration in a mouse model of fragile X syndrome. Nat. Commun. 10, 4813 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Ferron, L., Nieto-Rostro, M., Cassidy, J. S. & Dolphin, A. C. Fragile X mental retardation protein controls synaptic vesicle exocytosis by modulating N-type calcium channel density. Nat. Commun. 5, 3628 (2014). This study demonstrates that FMRP regulates surface expression of N-type VGCCs, and thus neurotransmitter release, in peripheral sensory neurons via protein–protein interactions.

    Article  PubMed  CAS  Google Scholar 

  61. Ferron, L. et al. FMRP regulates presynaptic localization of neuronal voltage gated calcium channels. Neurobiol. Dis. 138, 104779 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Deng, P. Y. et al. FMRP regulates neurotransmitter release and synaptic information transmission by modulating action potential duration via BK channels. Neuron 77, 696–711 (2013). This study presents initial evidence that FMRP directly interacts with BK channels to regulate neurotransmitter release in central neurons, which provides the rationale for investigating the BK channel as a promising therapeutic target to treat numerous excitability-related deficits in FXS.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Deng, P. Y., Sojka, D. & Klyachko, V. A. Abnormal presynaptic short-term plasticity and information processing in a mouse model of fragile X syndrome. J. Neurosci. 31, 10971–10982 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Zhang, N. et al. Decreased surface expression of the δ subunit of the GABAA receptor contributes to reduced tonic inhibition in dentate granule cells in a mouse model of fragile X syndrome. Exp. Neurol. 297, 168–178 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Yang, Y. M. et al. Identification of a molecular locus for normalizing dysregulated GABA release from interneurons in the fragile X brain. Mol. Psychiatry 25, 2017–2035 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Curia, G., Papouin, T., Seguela, P. & Avoli, M. Downregulation of tonic GABAergic inhibition in a mouse model of fragile X syndrome. Cereb. Cortex 19, 1515–1520 (2009).

    Article  PubMed  Google Scholar 

  67. Darnell, J. C. et al. Fragile X mental retardation protein targets G quartet mRNAs important for neuronal function. Cell 107, 489–499 (2001).

    Article  CAS  PubMed  Google Scholar 

  68. Strumbos, J. G., Brown, M. R., Kronengold, J., Polley, D. B. & Kaczmarek, L. K. Fragile X mental retardation protein is required for rapid experience-dependent regulation of the potassium channel Kv3.1b. J. Neurosci. 30, 10263–10271 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Strumbos, J. G., Polley, D. B. & Kaczmarek, L. K. Specific and rapid effects of acoustic stimulation on the tonotopic distribution of Kv3.1b potassium channels in the adult rat. Neuroscience 167, 567–572 (2010).

    Article  CAS  PubMed  Google Scholar 

  70. Rudy, B. & McBain, C. J. Kv3 channels: voltage-gated K+ channels designed for high-frequency repetitive firing. Trends Neurosci. 24, 517–526 (2001).

    Article  CAS  PubMed  Google Scholar 

  71. Kim, G. E. & Kaczmarek, L. K. Emerging role of the KCNT1 Slack channel in intellectual disability. Front. Cell Neurosci. 8, 209 (2014).

    PubMed  PubMed Central  Google Scholar 

  72. Brown, M. R. et al. Fragile X mental retardation protein controls gating of the sodium-activated potassium channel Slack. Nat. Neurosci. 13, 819–821 (2010). This seminal study provides the first evidence that FMRP directly regulates ion channel activity through protein–protein interactions, which opens a new field investigating FMRP’s physiological role in controlling ion channel function.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Zhang, Y. et al. Regulation of neuronal excitability by interaction of fragile X mental retardation protein with Slack potassium channels. J. Neurosci. 32, 15318–15327 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Contet, C., Goulding, S. P., Kuljis, D. A. & Barth, A. L. BK channels in the central nervous system. Int. Rev. Neurobiol. 128, 281–342 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Salkoff, L., Butler, A., Ferreira, G., Santi, C. & Wei, A. High-conductance potassium channels of the SLO family. Nat. Rev. Neurosci. 7, 921–931 (2006).

    Article  CAS  PubMed  Google Scholar 

  76. Myrick, L. K. et al. Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures. Proc. Natl Acad. Sci. USA 112, 949–956 (2015). This study shows that loss of the translation-independent functions of FMRP is linked with a subset of FXS clinical features, suggesting that domain-specific functions of FMRP in presynaptic and postsynaptic compartments may contribute to different aspects of FXS pathophysiology.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Hebert, B. et al. Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by a BKCa channel opener molecule. Orphanet J. Rare Dis. 9, 124 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Short, B. FMRP differentially regulates BK channels. J. Gen. Physiol. 152, e202012634 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Contractor, A. Broadening roles for FMRP: big news for big potassium (BK) channels. Neuron 77, 601–603 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Kshatri, A. et al. Differential regulation of BK channels by fragile X mental retardation protein. J. Gen. Physiol. 152, e201912502 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Telias, M., Kuznitsov-Yanovsky, L., Segal, M. & Ben-Yosef, D. Functional deficiencies in fragile X neurons derived from human embryonic stem cells. J. Neurosci. 35, 15295–15306 (2015). This study presents an extensive functional analysis of FXS neurons derived in vitro from embryonic stem cells of individuals with FXS that provides a useful tool for studying molecular mechanisms underlying the impaired neuronal functions in FXS.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Diaz, J., Scheiner, C. & Leon, E. Presentation of a recurrent FMR1 missense mutation (R138Q) in an affected female. Transl Sci. Rare Dis. 3, 139–144 (2018).

    Google Scholar 

  83. Prieto, M. et al. Missense mutation of Fmr1 results in impaired AMPAR-mediated plasticity and socio-cognitive deficits in mice. Nat. Commun. 12, 1557 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Carreno-Munoz, M. I. et al. Potential involvement of impaired BKCa channel function in sensory defensiveness and some behavioral disturbances induced by unfamiliar environment in a mouse model of fragile X syndrome. Neuropsychopharmacology 43, 492–502 (2018).

    Article  CAS  PubMed  Google Scholar 

  85. Bean, B. P. The action potential in mammalian central neurons. Nat. Rev. Neurosci. 8, 451–465 (2007).

    Article  CAS  PubMed  Google Scholar 

  86. Dwivedi, D., Chattarji, S. & Bhalla, U. S. Impaired reliability and precision of spiking in adults but not juveniles in a mouse model of fragile X syndrome. eNeuro 6, ENEURO.0217-19.2019 (2019).

    Article  Google Scholar 

  87. Catterall, W. A. Voltage-gated calcium channels. Cold Spring Harb. Perspect. Biol. 3, a003947 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Danesi, C. et al. Increased calcium influx through l-type calcium channels in human and mouse neural progenitors lacking fragile X mental retardation protein. Stem Cell Rep. 11, 1449–1461 (2018).

    Article  CAS  Google Scholar 

  89. Castagnola, S. et al. New insights into the role of Cav2 protein family in calcium flux deregulation in Fmr1-KO neurons. Front. Mol. Neurosci. 11, 342 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Gray, E. E. et al. Disruption of GpI mGluR-dependent Cav2.3 translation in a mouse model of fragile X syndrome. J. Neurosci. 39, 7453–7464 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Zhan, X. et al. FMRP1–297-tat restores ion channel and synaptic function in a model of fragile X syndrome. Nat. Commun. 11, 2755 (2020). This study shows that FMRP is part of a Cav3–Kv4 ion channel complex in cerebellar neurons, and describes a promising tat-conjugate approach to reintroduce an FMRP fragment to improve function in the cerebellum on multiple levels (channels, synapses, behaviour) in an FXS mouse model.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Nanou, E., Scheuer, T. & Catterall, W. A. Calcium sensor regulation of the CaV2.1 Ca2+ channel contributes to long-term potentiation and spatial learning. Proc. Natl Acad. Sci. USA 113, 13209–13214 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Cao, Y. Q. et al. Presynaptic Ca2+ channels compete for channel type-preferring slots in altered neurotransmission arising from Ca2+ channelopathy. Neuron 43, 387–400 (2004).

    Article  CAS  PubMed  Google Scholar 

  94. Darnell, J. C. et al. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146, 247–261 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Gross, C., Yao, X., Pong, D. L., Jeromin, A. & Bassell, G. J. Fragile X mental retardation protein regulates protein expression and mRNA translation of the potassium channel Kv4.2. J. Neurosci. 31, 5693–5698 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Lee, H. Y. et al. Bidirectional regulation of dendritic voltage-gated potassium channels by the fragile X mental retardation protein. Neuron 72, 630–642 (2011). Together with Gross et al. (2011), this study shows that FMRP regulates Kv4.2 channel expression with implications for altered dendritic excitability and plasticity in an FXS mouse model.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Routh, B. N., Johnston, D. & Brager, D. H. Loss of functional A-type potassium channels in the dendrites of CA1 pyramidal neurons from a mouse model of fragile X syndrome. J. Neurosci. 33, 19442–19450 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Chen, L., Yun, S. W., Seto, J., Liu, W. & Toth, M. The fragile X mental retardation protein binds and regulates a novel class of mRNAs containing U rich target sequences. Neuroscience 120, 1005–1017 (2003).

    Article  CAS  PubMed  Google Scholar 

  99. Gereau, R. W. T. & Conn, P. J. Multiple presynaptic metabotropic glutamate receptors modulate excitatory and inhibitory synaptic transmission in hippocampal area CA1. J. Neurosci. 15, 6879–6889 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Shah, M. M. Cortical HCN channels: function, trafficking and plasticity. J. Physiol. 592, 2711–2719 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Brandalise, F. et al. Fragile X mental retardation protein bidirectionally controls dendritic Ih in a cell-type specific manner between mouse hippocampus and prefrontal cortex. J. Neurosci. 40, 5327–5340 (2020). This study shows that FMRP regulates HCN channels via a cell-autonomous, protein–protein interaction and regulates its targets in opposite directions depending on the cellular milieu.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Huber, K. M., Gallagher, S. M., Warren, S. T. & Bear, M. F. Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc. Natl Acad. Sci. USA 99, 7746–7750 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Li, J., Pelletier, M. R., Perez Velazquez, J. L. & Carlen, P. L. Reduced cortical synaptic plasticity and GluR1 expression associated with fragile X mental retardation protein deficiency. Mol. Cell Neurosci. 19, 138–151 (2002).

    Article  PubMed  CAS  Google Scholar 

  104. Larson, J., Jessen, R. E., Kim, D., Fine, A. K. & du Hoffmann, J. Age-dependent and selective impairment of long-term potentiation in the anterior piriform cortex of mice lacking the fragile X mental retardation protein. J. Neurosci. 25, 9460–9469 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Hu, H. et al. Ras signaling mechanisms underlying impaired GluR1-dependent plasticity associated with fragile X syndrome. J. Neurosci. 28, 7847–7862 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Lim, C. S. et al. Pharmacological rescue of Ras signaling, GluA1-dependent synaptic plasticity, and learning deficits in a fragile X model. Genes Dev. 28, 273–289 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Guo, W. et al. Fragile X proteins FMRP and FXR2P control synaptic GluA1 expression and neuronal maturation via distinct mechanisms. Cell Rep. 11, 1651–1666 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Berry-Kravis, E. et al. Effect of CX516, an AMPA-modulating compound, on cognition and behavior in fragile X syndrome: a controlled trial. J. Child Adolesc. Psychopharmacol. 16, 525–540 (2006).

    Article  PubMed  Google Scholar 

  109. Schutt, J., Falley, K., Richter, D., Kreienkamp, H. J. & Kindler, S. Fragile X mental retardation protein regulates the levels of scaffold proteins and glutamate receptors in postsynaptic densities. J. Biol. Chem. 284, 25479–25487 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Edbauer, D. et al. Regulation of synaptic structure and function by FMRP-associated microRNAs miR-125b and miR-132. Neuron 65, 373–384 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Yun, S. H. & Trommer, B. L. Fragile X mice: reduced long-term potentiation and N-methyl-d-aspartate receptor-mediated neurotransmission in dentate gyrus. J. Neurosci. Res. 89, 176–182 (2011).

    Article  CAS  PubMed  Google Scholar 

  112. Bostrom, C. A. et al. Rescue of NMDAR-dependent synaptic plasticity in Fmr1 knock-out mice. Cereb. Cortex 25, 271–279 (2015).

    Article  CAS  PubMed  Google Scholar 

  113. Bostrom, C. et al. Hippocampal dysfunction and cognitive impairment in fragile-X syndrome. Neurosci. Biobehav. Rev. 68, 563–574 (2016).

    Article  CAS  PubMed  Google Scholar 

  114. Eadie, B. D., Cushman, J., Kannangara, T. S., Fanselow, M. S. & Christie, B. R. NMDA receptor hypofunction in the dentate gyrus and impaired context discrimination in adult Fmr1 knockout mice. Hippocampus 22, 241–254 (2012).

    Article  CAS  PubMed  Google Scholar 

  115. Yau, S. Y., Bettio, L., Chiu, J., Chiu, C. & Christie, B. R. Fragile-X syndrome is associated with NMDA receptor hypofunction and reduced dendritic complexity in mature dentate granule cells. Front. Mol. Neurosci. 11, 495 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Smart, T. G. & Stephenson, F. A. A half century of γ-aminobutyric acid. Brain Neurosci. Adv. 3, 2398212819858249 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Van der Aa, N. & Kooy, R. F. GABAergic abnormalities in the fragile X syndrome. Eur. J. Paediatr. Neurol. 24, 100–104 (2020).

    Article  PubMed  Google Scholar 

  118. Gantois, I. et al. Expression profiling suggests underexpression of the GABAA receptor subunit δ in the fragile X knockout mouse model. Neurobiol. Dis. 21, 346–357 (2006).

    Article  CAS  PubMed  Google Scholar 

  119. D’Hulst, C. et al. Decreased expression of the GABAA receptor in fragile X syndrome. Brain Res. 1121, 238–245 (2006). Together with Gantois et al. (2006), this study reports hypofunction of GABAARs in an FXS mouse model, which points to the GABAAR as a promising target for treatment of the behavioural and epileptic phenotypes associated with FXS.

    Article  PubMed  CAS  Google Scholar 

  120. Sabanov, V. et al. Impaired GABAergic inhibition in the hippocampus of Fmr1 knockout mice. Neuropharmacology 116, 71–81 (2017).

    Article  CAS  PubMed  Google Scholar 

  121. Vien, T. N. et al. Compromising the phosphodependent regulation of the GABAAR β3 subunit reproduces the core phenotypes of autism spectrum disorders. Proc. Natl Acad. Sci. USA 112, 14805–14810 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. D’Hulst, C., Atack, J. R. & Kooy, R. F. The complexity of the GABAA receptor shapes unique pharmacological profiles. Drug Discov. Today 14, 866–875 (2009).

    Article  PubMed  CAS  Google Scholar 

  123. Adusei, D. C., Pacey, L. K., Chen, D. & Hampson, D. R. Early developmental alterations in GABAergic protein expression in fragile X knockout mice. Neuropharmacology 59, 167–171 (2010).

    Article  CAS  PubMed  Google Scholar 

  124. El Idrissi, A. et al. Decreased GABAA receptor expression in the seizure-prone fragile X mouse. Neurosci. Lett. 377, 141–146 (2005).

    Article  CAS  PubMed  Google Scholar 

  125. D’Hulst, C. et al. Positron emission tomography (PET) quantification of GABAA receptors in the brain of fragile X patients. PLoS ONE 10, e0131486 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Braat, S. et al. The GABAA receptor is an FMRP target with therapeutic potential in fragile X syndrome. Cell Cycle 14, 2985–2995 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Davidovic, L. et al. A metabolomic and systems biology perspective on the brain of the fragile X syndrome mouse model. Genome Res. 21, 2190–2202 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Huntsman, M. M. & Kooy, R. F. in Fragile X Syndrome: From Genetics to Targeted Treatment (eds Willemsen, R. & Kooy, R. F.) 205–215 (Academic Press, 2017).

  129. Braat, S. & Kooy, R. F. Insights into GABAAergic system deficits in fragile X syndrome lead to clinical trials. Neuropharmacology 88, 48–54 (2014).

    Article  PubMed  CAS  Google Scholar 

  130. Hutson, R. L., Thompson, R. L., Bantel, A. P. & Tessier, C. R. Acamprosate rescues neuronal defects in the Drosophila model of fragile X syndrome. Life Sci. 195, 65–70 (2018).

    Article  CAS  PubMed  Google Scholar 

  131. Schaefer, T. L. et al. Acamprosate in a mouse model of fragile X syndrome: modulation of spontaneous cortical activity, ERK1/2 activation, locomotor behavior, and anxiety. J. Neurodev. Disord. 9, 6 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Erickson, C. A., Mullett, J. E. & McDougle, C. J. Brief report: acamprosate in fragile X syndrome. J. Autism Dev. Disord. 40, 1412–1416 (2010).

    Article  PubMed  Google Scholar 

  133. Erickson, C. A. et al. Impact of acamprosate on plasma amyloid-β precursor protein in youth: a pilot analysis in fragile X syndrome-associated and idiopathic autism spectrum disorder suggests a pharmacodynamic protein marker. J. Psychiatr. Res. 59, 220–228 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Ligsay, A. et al. A randomized double-blind, placebo-controlled trial of ganaxolone in children and adolescents with fragile X syndrome. J. Neurodev. Disord. 9, 26 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Di Miceli, M. & Gronier, B. Pharmacology, systematic review and recent clinical trials of metadoxine. Rev. Recent Clin. Trials 13, 114–125 (2018).

    Article  PubMed  CAS  Google Scholar 

  136. Silverman, J. L. et al. GABAB receptor agonist R-baclofen reverses social deficits and reduces repetitive behavior in two mouse models of autism. Neuropsychopharmacology 40, 2228–2239 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Sinclair, D. et al. GABA-B agonist baclofen normalizes auditory-evoked neural oscillations and behavioral deficits in the Fmr1 knockout mouse model of fragile X syndrome. eNeuro 4, ENEURO.0380-16.2017 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Stoppel, L. J. et al. R-Baclofen reverses cognitive deficits and improves social interactions in two lines of 16p11.2 deletion mice. Neuropsychopharmacology 43, 513–524 (2018).

    Article  CAS  PubMed  Google Scholar 

  139. Henderson, C. et al. Reversal of disease-related pathologies in the fragile X mouse model by selective activation of GABAB receptors with arbaclofen. Sci. Transl Med. 4, 152ra128 (2012).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  140. Berry-Kravis, E. M. et al. Effects of STX209 (arbaclofen) on neurobehavioral function in children and adults with fragile X syndrome: a randomized, controlled, phase 2 trial. Sci. Transl Med. 4, 152ra127 (2012).

    Article  PubMed  CAS  Google Scholar 

  141. Erickson, C. A. et al. STX209 (arbaclofen) for autism spectrum disorders: an 8-week open-label study. J. Autism Dev. Disord. 44, 958–964 (2014).

    Article  PubMed  Google Scholar 

  142. Represa, A. & Ben-Ari, Y. Trophic actions of GABA on neuronal development. Trends Neurosci. 28, 278–283 (2005).

    Article  CAS  PubMed  Google Scholar 

  143. Liu, R., Wang, J., Liang, S., Zhang, G. & Yang, X. Role of NKCC1 and KCC2 in epilepsy: from expression to function. Front. Neurol. 10, 1407 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  144. He, Q., Nomura, T., Xu, J. & Contractor, A. The developmental switch in GABA polarity is delayed in fragile X mice. J. Neurosci. 34, 446–450 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. He, Q. et al. Critical period inhibition of NKCC1 rectifies synapse plasticity in the somatosensory cortex and restores adult tactile response maps in fragile X mice. Mol. Psychiatry 24, 1732–1747 (2019). Together with He et al. (2014), this study provides strong evidence that targeting the Cl– transporter NKCC1 during the critical period restores synapse development in cortical neurons and produces a long-lasting correction of somatosensory circuit function in FXS mice.

    Article  CAS  PubMed  Google Scholar 

  146. Tyzio, R. et al. Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring. Science 343, 675–679 (2014).

    Article  CAS  PubMed  Google Scholar 

  147. Hodges, J. L. et al. Astrocytic contributions to synaptic and learning abnormalities in a mouse model of fragile X syndrome. Biol. Psychiatry 82, 139–149 (2017).

    Article  CAS  PubMed  Google Scholar 

  148. Cheng, C., Lau, S. K. & Doering, L. C. Astrocyte-secreted thrombospondin-1 modulates synapse and spine defects in the fragile X mouse model. Mol. Brain 9, 74 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  149. Higashimori, H. et al. Selective deletion of astroglial FMRP dysregulates glutamate transporter GLT1 and contributes to fragile X syndrome phenotypes in vivo. J. Neurosci. 36, 7079–7094 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Guglielmi, L. et al. Update on the implication of potassium channels in autism: K+ channel autism spectrum disorder. Front. Cell Neurosci. 9, 34 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Schmunk, G. & Gargus, J. J. Channelopathy pathogenesis in autism spectrum disorders. Front. Genet. 4, 222 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Lee, H., Lin, M. C., Kornblum, H. I., Papazian, D. M. & Nelson, S. F. Exome sequencing identifies de novo gain of function missense mutation in KCND2 in identical twins with autism and seizures that slows potassium channel inactivation. Hum. Mol. Genet. 23, 3481–3489 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Lin, M. A., Cannon, S. C. & Papazian, D. M. Kv4.2 autism and epilepsy mutation enhances inactivation of closed channels but impairs access to inactivated state after opening. Proc. Natl Acad. Sci. USA 115, E3559–E3568 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Laumonnier, F. et al. Association of a functional deficit of the BKCa channel, a synaptic regulator of neuronal excitability, with autism and mental retardation. Am. J. Psychiatry 163, 1622–1629 (2006).

    Article  PubMed  Google Scholar 

  155. Kruth, K. A., Grisolano, T. M., Ahern, C. A. & Williams, A. J. SCN2A channelopathies in the autism spectrum of neuropsychiatric disorders: a role for pluripotent stem cells? Mol. Autism 11, 23 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Orefice, L. L. et al. Targeting peripheral somatosensory neurons to improve tactile-related phenotypes in ASD models. Cell 178, 867–886 (2019). This study reveals a potential therapeutic strategy targeting excitation/inhibition imbalance in peripheral mechanosensory circuits to treat tactile over-reactivity and select ASD-related behaviours.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Liao, L., Park, S. K., Xu, T., Vanderklish, P. & Yates, J. R. 3rd Quantitative proteomic analysis of primary neurons reveals diverse changes in synaptic protein content in Fmr1 knockout mice. Proc. Natl Acad. Sci. USA 105, 15281–15286 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Myrick, L. K., Hashimoto, H., Cheng, X. & Warren, S. T. Human FMRP contains an integral tandem Agenet (Tudor) and KH motif in the amino terminal domain. Hum. Mol. Genet. 24, 1733–1740 (2015).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported in part by R35 grant NS111596 to V.A.K. from the National Institute of Neurological Disorders and Stroke (NINDS). The authors apologize to colleagues whose work could not be cited in this Review due to space limitations. Figures 1 and 2 were created with BioRender.com.

Author information

Authors and Affiliations

  1. Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, MO, USA

    Pan-Yue Deng & Vitaly A. Klyachko

Authors
  1. Pan-Yue Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vitaly A. Klyachko
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

P.-Y.D. and V.A.K. contributed equally to this work.

Corresponding author

Correspondence to Vitaly A. Klyachko.

Ethics declarations

Competing interests

The authors declare no competing interests

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Referee accreditation

Nature Reviews Neuroscience thanks L. Kaczmarek and R. Hagerman, and the other anonymous reviewer(s), for their contribution to the peer review of this work.

Glossary

Macroorchidism

A condition in which males have abnormally large testes.

Channelopathies

A heterogeneous group of disorders resulting from the dysfunction of ion channels, which can be caused by mutations either in genes encoding channels themselves or in related factors that regulate ion channels.

Hyperexcitability

An abnormal state of a neuron characterized by increased probability of firing action potentials in response to an input.

Audiogenic seizures

Seizures that are triggered by acoustic stimulation.

UP states

One of the two preferred subthreshold membrane potentials of a neuron, characterized by a more depolarized state during which it is easier for a neuron to fire action potentials.

Feedforward inhibition

A ubiquitous unitary motif in the organization of neural circuits in which an excitatory neuron excites an inhibitory interneuron, which then in turn inhibits a downstream excitatory cell (or cells).

Hyperextensibility

The ability of the finger joints to move beyond their normal range of motion.

Intratelencephalic projecting pyramidal cells

Telencephalic pyramidal cells whose axons project to regions within the telencepalon.

Critical period

A time period during early postnatal life when the development and maturation of functional properties of the brain is strongly dependent on experiences or environmental influences.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Deng, PY., Klyachko, V.A. Channelopathies in fragile X syndrome. Nat Rev Neurosci 22, 275–289 (2021). https://doi.org/10.1038/s41583-021-00445-9

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41583-021-00445-9

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing