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.

The role of GABAergic signalling in neurodevelopmental disorders

Abstract

GABAergic inhibition shapes the connectivity, activity and plasticity of the brain. A series of exciting new discoveries provides compelling evidence that disruptions in a number of key facets of GABAergic inhibition have critical roles in the aetiology of neurodevelopmental disorders (NDDs). These facets include the generation, migration and survival of GABAergic neurons, the formation of GABAergic synapses and circuit connectivity, and the dynamic regulation of the efficacy of GABAergic signalling through neuronal chloride transporters. In this Review, we discuss recent work that elucidates the functions and dysfunctions of GABAergic signalling in health and disease, that uncovers the contribution of GABAergic neural circuit dysfunction to NDD aetiology and that leverages such mechanistic insights to advance precision medicine for the treatment of NDDs.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Development of the GABAergic signalling system.
Fig. 2: Pathogenic mechanisms underlying neurodevelopmental disorders.
Fig. 3: Therapeutic opportunities at the genetic level for managing NDDs.
Fig. 4: Therapeutic opportunities at the molecular level for managing NDDs.
Fig. 5: Therapeutic opportunities at the circuit level for managing NDDs.
Fig. 6: Therapeutic and diagnostic opportunities at the individual level for neurodevelopmental disorders.

References

  1. 1.

    Boyle, C. A. et al. Trends in the prevalence of developmental disabilities in US children, 1997–2008. Pediatrics 127, 1034–1042 (2011).

    PubMed  Article  Google Scholar 

  2. 2.

    Satterstrom, F. K. et al. Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism. Cell 180, 568–584 e523 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Wamsley, B. & Fishell, G. Genetic and activity-dependent mechanisms underlying interneuron diversity. Nat. Rev. Neurosci. 18, 299–309 (2017).

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Marin, O. Interneuron dysfunction in psychiatric disorders. Nat. Rev. Neurosci. 13, 107–120 (2012).

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Tasic, B. et al. Shared and distinct transcriptomic cell types across neocortical areas. Nature 563, 72–78 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Nicholas, C. R. et al. Functional maturation of hPSC-derived forebrain interneurons requires an extended timeline and mimics human neural development. Cell Stem Cell 12, 573–586 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Yang, N. et al. Generation of pure GABAergic neurons by transcription factor programming. Nat. Methods 14, 621–628 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    Lim, L., Mi, D., Llorca, A. & Marin, O. Development and functional diversification of cortical interneurons. Neuron 100, 294–313 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Marin, O. & Rubenstein, J. L. A long, remarkable journey: tangential migration in the telencephalon. Nat. Rev. Neurosci. 2, 780–790 (2001).

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Bortone, D. & Polleux, F. KCC2 expression promotes the termination of cortical interneuron migration in a voltage-sensitive calcium-dependent manner. Neuron 62, 53–71 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    De Marco Garcia, N. V., Karayannis, T. & Fishell, G. Neuronal activity is required for the development of specific cortical interneuron subtypes. Nature 472, 351–355 (2011). This article reveals the connection between neuronal activity and cortical cellular architecture — specifically, the integration of GABAergic inhibitory neurons into brain circuits.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  12. 12.

    Francavilla, R. et al. Alterations in intrinsic and synaptic properties of hippocampal CA1 VIP interneurons during aging. Front. Cell Neurosci. 14, 554405 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Bartolini, G., Ciceri, G. & Marin, O. Integration of GABAergic interneurons into cortical cell assemblies: lessons from embryos and adults. Neuron 79, 849–864 (2013).

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Pfeffer, C. K., Xue, M., He, M., Huang, Z. J. & Scanziani, M. Inhibition of inhibition in visual cortex: the logic of connections between molecularly distinct interneurons. Nat. Neurosci. 16, 1068–1076 (2013). This article describes a number of distinct connectivity patterns between three major cortical inhibitory neuron subtypes, which has implications for understanding the connectivity and computational logic of cortical circuits.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Zhang, C. et al. Neurexins physically and functionally interact with GABAA receptors. Neuron 66, 403–416 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Dong, N., Qi, J. & Chen, G. Molecular reconstitution of functional GABAergic synapses with expression of neuroligin-2 and GABAA receptors. Mol. Cell Neurosci. 35, 14–23 (2007).

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Craig, A. M., Banker, G., Chang, W., McGrath, M. E. & Serpinskaya, A. S. Clustering of gephyrin at GABAergic but not glutamatergic synapses in cultured rat hippocampal neurons. J. Neurosci. 16, 3166–3177 (1996).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Papadopoulos, T. & Soykan, T. The role of collybistin in gephyrin clustering at inhibitory synapses: facts and open questions. Front. Cell Neurosci. 5, 11 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Lee, V. & Maguire, J. The impact of tonic GABAA receptor-mediated inhibition on neuronal excitability varies across brain region and cell type. Front. Neural Circuits 8, 3 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  20. 20.

    Caraiscos, V. B. et al. Tonic inhibition in mouse hippocampal CA1 pyramidal neurons is mediated by α5 subunit-containing γ-aminobutyric acid type A receptors. Proc. Natl Acad. Sci. USA 101, 3662–3667 (2004).

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Wei, W., Zhang, N., Peng, Z., Houser, C. R. & Mody, I. Perisynaptic localization of δ subunit-containing GABAA receptors and their activation by GABA spillover in the mouse dentate gyrus. J. Neurosci. 23, 10650–10661 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Datta, D., Arion, D. & Lewis, D. A. Developmental expression patterns of GABAA receptor subunits in layer 3 and 5 pyramidal cells of monkey prefrontal cortex. Cereb. Cortex 25, 2295–2305 (2015).

    PubMed  Article  Google Scholar 

  23. 23.

    Scimemi, A. Structure, function, and plasticity of GABA transporters. Front. Cell Neurosci. 8, 161 (2014).

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Lee, S. et al. Channel-mediated tonic GABA release from glia. Science 330, 790–796 (2010).

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Pavlov, I., Savtchenko, L. P., Kullmann, D. M., Semyanov, A. & Walker, M. C. Outwardly rectifying tonically active GABAA receptors in pyramidal cells modulate neuronal offset, not gain. J. Neurosci. 29, 15341–15350 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Chalifoux, J. R. & Carter, A. G. GABAB receptor modulation of synaptic function. Curr. Opin. Neurobiol. 21, 339–344 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Ben-Ari, Y., Khalilov, I., Kahle, K. T. & Cherubini, E. The GABA excitatory/inhibitory shift in brain maturation and neurological disorders. Neuroscientist 18, 467–486 (2012).

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    Chen, G., Trombley, P. Q. & van den Pol, A. N. Excitatory actions of GABA in developing rat hypothalamic neurones. J. Physiol. 494, 451–464 (1996).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Paulus, W. & Rothwell, J. C. Membrane resistance and shunting inhibition: where biophysics meets state-dependent human neurophysiology. J. Physiol. 594, 2719–2728 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Rivera, C. et al. The K+/Cl- co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature 397, 251–255 (1999). This is the first article to demonstrate that KCC2 is the main chloride extruder that mediates the hyperpolarizing GABAergic synaptic transmission in functionally mature neurons.

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Bao, H. et al. Long-range GABAergic inputs regulate neural stem cell quiescence and control adult hippocampal neurogenesis. Cell Stem Cell 21, 604–617 e605 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Banke, T. G. & McBain, C. J. GABAergic input onto CA3 hippocampal interneurons remains shunting throughout development. J. Neurosci. 26, 11720–11725 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Tang, X. et al. KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome. Proc. Natl Acad. Sci. USA 113, 751–756 (2016). This work uncovers a link between reduction in KCC2 expression and the impaired GABA functional switch in a human induced pluripotent stem cell-derived neuronal model of Rett syndrome, indicating a pathological mechanism underlying neural circuit function abnormalities observed in patients.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Vanhatalo, S. et al. Slow endogenous activity transients and developmental expression of K+-Cl cotransporter 2 in the immature human cortex. Eur. J. Neurosci. 22, 2799–2804 (2005).

    PubMed  Article  Google Scholar 

  35. 35.

    Dzhala, V. I. et al. NKCC1 transporter facilitates seizures in the developing brain. Nat. Med. 11, 1205–1213 (2005).

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Wang, D. D. & Kriegstein, A. R. GABA regulates excitatory synapse formation in the neocortex via NMDA receptor activation. J. Neurosci. 28, 5547–5558 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Nakanishi, K., Yamada, J., Takayama, C., Oohira, A. & Fukuda, A. NKCC1 activity modulates formation of functional inhibitory synapses in cultured neocortical neurons. Synapse 61, 138–149 (2007).

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Pfeffer, C. K. et al. NKCC1-dependent GABAergic excitation drives synaptic network maturation during early hippocampal development. J. Neurosci. 29, 3419–3430 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Li, H. et al. KCC2 interacts with the dendritic cytoskeleton to promote spine development. Neuron 56, 1019–1033 (2007).

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Gauvain, G. et al. The neuronal K-Cl cotransporter KCC2 influences postsynaptic AMPA receptor content and lateral diffusion in dendritic spines. Proc. Natl Acad. Sci. USA 108, 15474–15479 (2011).

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Chevy, Q. et al. KCC2 gates activity-driven AMPA receptor traffic through cofilin phosphorylation. J. Neurosci. 35, 15772–15786 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    Llano, O. et al. KCC2 regulates actin dynamics in dendritic spines via interaction with β-PIX. J. Cell Biol. 209, 671–686 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Mahadevan, V. et al. Native KCC2 interactome reveals PACSIN1 as a critical regulator of synaptic inhibition. eLife 6, e28270 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Karnani, M. M. et al. Opening holes in the blanket of inhibition: localized lateral disinhibition by VIP interneurons. J. Neurosci. 36, 3471–3480 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Karnani, M. M., Agetsuma, M. & Yuste, R. A blanket of inhibition: functional inferences from dense inhibitory connectivity. Curr. Opin. Neurobiol. 26, 96–102 (2014).

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Fino, E. & Yuste, R. Dense inhibitory connectivity in neocortex. Neuron 69, 1188–1203 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Packer, A. M. & Yuste, R. Dense, unspecific connectivity of neocortical parvalbumin-positive interneurons: a canonical microcircuit for inhibition? J. Neurosci. 31, 13260–13271 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Ben-Ari, Y., Gaiarsa, J. L., Tyzio, R. & Khazipov, R. GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations. Physiol. Rev. 87, 1215–1284 (2007).

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Kasyanov, A. M., Safiulina, V. F., Voronin, L. L. & Cherubini, E. GABA-mediated giant depolarizing potentials as coincidence detectors for enhancing synaptic efficacy in the developing hippocampus. Proc. Natl Acad. Sci. USA 101, 3967–3972 (2004).

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Buzsaki, G. & Draguhn, A. Neuronal oscillations in cortical networks. Science 304, 1926–1929 (2004).

    CAS  Article  Google Scholar 

  51. 51.

    Colgin, L. L. & Moser, E. I. Gamma oscillations in the hippocampus. Physiology 25, 319–329 (2010).

    PubMed  Article  Google Scholar 

  52. 52.

    Chen, G. et al. Distinct inhibitory circuits orchestrate cortical beta and gamma band oscillations. Neuron 96, 1403–1418 e1406 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Brockmann, M. D., Poschel, B., Cichon, N. & Hanganu-Opatz, I. L. Coupled oscillations mediate directed interactions between prefrontal cortex and hippocampus of the neonatal rat. Neuron 71, 332–347 (2011).

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Le Magueresse, C. & Monyer, H. GABAergic interneurons shape the functional maturation of the cortex. Neuron 77, 388–405 (2013).

    PubMed  Article  CAS  Google Scholar 

  55. 55.

    Hsu, A., Luebke, J. I. & Medalla, M. Comparative ultrastructural features of excitatory synapses in the visual and frontal cortices of the adult mouse and monkey. J. Comp. Neurol. 525, 2175–2191 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56.

    Cline, H. Synaptogenesis: a balancing act between excitation and inhibition. Curr. Biol. 15, R203–R205 (2005).

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Rannals, M. D. & Kapur, J. Homeostatic strengthening of inhibitory synapses is mediated by the accumulation of GABAA receptors. J. Neurosci. 31, 17701–17712 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    Hanson, E. et al. Tonic activation of GluN2C/GluN2D-containing NMDA receptors by ambient glutamate facilitates cortical interneuron maturation. J. Neurosci. 39, 3611–3626 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Southwell, D. G. et al. Intrinsically determined cell death of developing cortical interneurons. Nature 491, 109–113 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Wong, F. K. et al. Pyramidal cell regulation of interneuron survival sculpts cortical networks. Nature 557, 668–673 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Hensch, T. K. et al. Local GABA circuit control of experience-dependent plasticity in developing visual cortex. Science 282, 1504–1508 (1998). This is the first article to demonstrate the role of GABAergic inhibitory transmission in regulating the strength of experience-dependent plasticity and the developmental critical period window in the cortex.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    Fagiolini, M. et al. Specific GABAA circuits for visual cortical plasticity. Science 303, 1681–1683 (2004).

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    Deidda, G. et al. Early depolarizing GABA controls critical-period plasticity in the rat visual cortex. Nat. Neurosci. 18, 87–96 (2015).

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Davies, C. H., Starkey, S. J., Pozza, M. F. & Collingridge, G. L. GABA autoreceptors regulate the induction of LTP. Nature 349, 609–611 (1991).

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Paulsen, O. & Moser, E. I. A model of hippocampal memory encoding and retrieval: GABAergic control of synaptic plasticity. Trends Neurosci. 21, 273–278 (1998).

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Iwai, Y., Fagiolini, M., Obata, K. & Hensch, T. K. Rapid critical period induction by tonic inhibition in visual cortex. J. Neurosci. 23, 6695–6702 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    Tang, Y., Stryker, M. P., Alvarez-Buylla, A. & Espinosa, J. S. Cortical plasticity induced by transplantation of embryonic somatostatin or parvalbumin interneurons. Proc. Natl Acad. Sci. USA 111, 18339–18344 (2014).

    CAS  PubMed  Article  Google Scholar 

  68. 68.

    Harauzov, A. et al. Reducing intracortical inhibition in the adult visual cortex promotes ocular dominance plasticity. J. Neurosci. 30, 361–371 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Rubenstein, J. L. & Merzenich, M. M. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav. 2, 255–267 (2003). This is the first article to propose the hypothesis that a combination of genetic and environmental factors may have an important role in autism through disturbing the balance between excitation and inhibition (increasing E/I ratio).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

    Taylor, M. J. et al. Etiology of autism spectrum disorders and autistic traits over time. JAMA Psychiatry 77, 936–943 (2020).

    PubMed  Article  Google Scholar 

  71. 71.

    Chen, C. H. et al. Genetic analysis of GABRB3 as a candidate gene of autism spectrum disorders. Mol. Autism 5, 36 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  72. 72.

    Feng, J. et al. High frequency of neurexin 1β signal peptide structural variants in patients with autism. Neurosci. Lett. 409, 10–13 (2006).

    CAS  PubMed  Article  Google Scholar 

  73. 73.

    Gauthier, J. et al. Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia. Hum. Genet. 130, 563–573 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74.

    Vaags, A. K. et al. Rare deletions at the neurexin 3 locus in autism spectrum disorder. Am. J. Hum. Genet. 90, 133–141 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. 75.

    Chen, C. H., Lee, P. W., Liao, H. M. & Chang, P. K. Neuroligin 2 R215H mutant mice manifest anxiety, increased prepulse inhibition, and impaired spatial learning and memory. Front. Psychiatry 8, 257 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  76. 76.

    Prasad, A. et al. A discovery resource of rare copy number variations in individuals with autism spectrum disorder. G3 2, 1665–1685 (2012).

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    Lionel, A. C. et al. Rare exonic deletions implicate the synaptic organizer gephyrin (GPHN) in risk for autism, schizophrenia and seizures. Hum. Mol. Genet. 22, 2055–2066 (2013).

    CAS  PubMed  Article  Google Scholar 

  78. 78.

    Shimojima, K. et al. Loss-of-function mutation of collybistin is responsible for X-linked mental retardation associated with epilepsy. J. Hum. Genet. 56, 561–565 (2011).

    CAS  PubMed  Article  Google Scholar 

  79. 79.

    Johannesen, K. M. et al. Defining the phenotypic spectrum of SLC6A1 mutations. Epilepsia 59, 389–402 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. 80.

    Merner, N. D. et al. Regulatory domain or CpG site variation in SLC12A5, encoding the chloride transporter KCC2, in human autism and schizophrenia. Front. Cell Neurosci. 9, 386 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  81. 81.

    Carvill, G. L. et al. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat. Genet. 45, 825–830 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82.

    Coe, B. P. et al. Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity. Nat. Genet. 51, 106–116 (2019).

    CAS  PubMed  Article  Google Scholar 

  83. 83.

    Rosenfeld, J. A. et al. Genotype-phenotype analysis of TCF4 mutations causing Pitt-Hopkins syndrome shows increased seizure activity with missense mutations. Genet. Med. 11, 797–805 (2009).

    PubMed  Article  Google Scholar 

  84. 84.

    Lipton, J. O. & Sahin, M. The neurology of mTOR. Neuron 84, 275–291 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. 85.

    Machado, C. O. et al. Collybistin binds and inhibits mTORC1 signaling: a potential novel mechanism contributing to intellectual disability and autism. Eur. J. Hum. Genet. 24, 59–65 (2016).

    PubMed  Article  CAS  Google Scholar 

  86. 86.

    Kumar, S. et al. Impaired neurodevelopmental pathways in autism spectrum disorder: a review of signaling mechanisms and crosstalk. J. Neurodev. Disord. 11, 10 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. 87.

    Lynch, M. Rate, molecular spectrum, and consequences of human mutation. Proc. Natl Acad. Sci. USA 107, 961–968 (2010).

    CAS  PubMed  Article  Google Scholar 

  88. 88.

    Rodin, R. E. & Walsh, C. A. Somatic mutation in pediatric neurological diseases. Pediatr. Neurol. 87, 20–22 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  89. 89.

    Krupp, D. R. et al. Exonic mosaic mutations contribute risk for autism spectrum disorder. Am. J. Hum. Genet. 101, 369–390 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. 90.

    Kushima, I. et al. Comparative analyses of copy-number variation in autism spectrum disorder and schizophrenia reveal etiological overlap and biological insights. Cell Rep. 24, 2838–2856 (2018).

    CAS  PubMed  Article  Google Scholar 

  91. 91.

    Poduri, A. et al. Somatic activation of AKT3 causes hemispheric developmental brain malformations. Neuron 74, 41–48 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. 92.

    Sanders, S. J. et al. Insights into autism spectrum disorder genomic architecture and biology from 71 risk loci. Neuron 87, 1215–1233 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. 93.

    Korb, E. et al. Excess translation of epigenetic regulators contributes to fragile X syndrome and is alleviated by Brd4 inhibition. Cell 170, 1209–1223 e1220 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. 94.

    Fatemi, S. H., Reutiman, T. J., Folsom, T. D. & Thuras, P. D. GABAA receptor downregulation in brains of subjects with autism. J. Autism Dev. Disord. 39, 223–230 (2009).

    PubMed  Article  Google Scholar 

  95. 95.

    Fatemi, S. H. et al. Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices. Biol. Psychiatry 52, 805–810 (2002).

    CAS  PubMed  Article  Google Scholar 

  96. 96.

    Hernando-Herraez, I., Garcia-Perez, R., Sharp, A. J. & Marques-Bonet, T. DNA methylation: insights into human evolution. PLoS Genet. 11, e1005661 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  97. 97.

    Liu, X. S. et al. Rescue of fragile X syndrome neurons by DNA methylation editing of the FMR1 gene. Cell 172, 979–992 e976 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. 98.

    Berman, R. F. et al. Mouse models of the fragile X premutation and fragile X-associated tremor/ataxia syndrome. J. Neurodev. Disord. 6, 25 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  99. 99.

    Atladottir, H. O. et al. Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders. J. Autism Dev. Disord. 40, 1423–1430 (2010).

    PubMed  Article  Google Scholar 

  100. 100.

    Choi, G. B. et al. The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science 351, 933–939 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. 101.

    Shin Yim, Y. et al. Reversing behavioural abnormalities in mice exposed to maternal inflammation. Nature 549, 482–487 (2017).

    PubMed  Article  CAS  Google Scholar 

  102. 102.

    Li, Y., Zhou, Y., Peng, L. & Zhao, Y. Reduced protein expressions of cytomembrane GABAARβ3 at different postnatal developmental stages of rats exposed prenatally to valproic acid. Brain Res. 1671, 33–42 (2017).

    CAS  PubMed  Article  Google Scholar 

  103. 103.

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. 104.

    Savardi, A. et al. Discovery of a small molecule drug candidate for selective NKCC1 inhibition in brain disorders. Chem 6, 2073–2096 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. 105.

    Yeo, M. et al. Bisphenol A delays the perinatal chloride shift in cortical neurons by epigenetic effects on the Kcc2 promoter. Proc. Natl Acad. Sci. USA 110, 4315–4320 (2013).

    CAS  PubMed  Article  Google Scholar 

  106. 106.

    Li, Y. et al. Global transcriptional and translational repression in human-embryonic-stem-cell-derived Rett syndrome neurons. Cell Stem Cell 13, 446–458 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  107. 107.

    Castro, J. et al. Functional recovery with recombinant human IGF1 treatment in a mouse model of Rett syndrome. Proc. Natl Acad. Sci. USA 111, 9941–9946 (2014).

    CAS  PubMed  Article  Google Scholar 

  108. 108.

    Mellios, N. et al. MeCP2-regulated miRNAs control early human neurogenesis through differential effects on ERK and AKT signaling. Mol. Psychiatry 23, 1051–1065 (2018).

    CAS  PubMed  Article  Google Scholar 

  109. 109.

    Dong, F. et al. Deletion of CTNNB1 in inhibitory circuitry contributes to autism-associated behavioral defects. Hum. Mol. Genet. 25, 2738–2751 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Mohn, J. L. et al. Adenomatous polyposis coli protein deletion leads to cognitive and autism-like disabilities. Mol. Psychiatry 19, 1133–1142 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. 111.

    Chen, Y., Huang, W. C., Sejourne, J., Clipperton-Allen, A. E. & Page, D. T. Pten mutations alter brain growth trajectory and allocation of cell types through elevated β-catenin signaling. J. Neurosci. 35, 10252–10267 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. 112.

    Durak, O. et al. Chd8 mediates cortical neurogenesis via transcriptional regulation of cell cycle and Wnt signaling. Nat. Neurosci. 19, 1477–1488 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. 113.

    Banerjee, A. et al. Jointly reduced inhibition and excitation underlies circuit-wide changes in cortical processing in Rett syndrome. Proc. Natl Acad. Sci. USA 113, E7287–E7296 (2016).

    CAS  PubMed  Article  Google Scholar 

  114. 114.

    Zhang, W., Peterson, M., Beyer, B., Frankel, W. N. & Zhang, Z. W. Loss of MeCP2 from forebrain excitatory neurons leads to cortical hyperexcitation and seizures. J. Neurosci. 34, 2754–2763 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. 115.

    Kleschevnikov, A. M. et al. Deficits in cognition and synaptic plasticity in a mouse model of Down syndrome ameliorated by GABAB receptor antagonists. J. Neurosci. 32, 9217–9227 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. 116.

    Costa, A. C. & Grybko, M. J. Deficits in hippocampal CA1 LTP induced by TBS but not HFS in the Ts65Dn mouse: a model of Down syndrome. Neurosci. Lett. 382, 317–322 (2005).

    CAS  PubMed  Article  Google Scholar 

  117. 117.

    Deidda, G. et al. Reversing excitatory GABAAR signaling restores synaptic plasticity and memory in a mouse model of Down syndrome. Nat. Med. 21, 318–326 (2015). This study demonstrates that pharmacological reversal of excitatory GABA action with the NKCC1 blocker bumetanide rescues synaptic and behavioural abnormalities in a mouse model of Down syndrome, indicating that restoration of chloride homeostasis is a promising therapeutic avenue for treating neurodevelopmental disorders.

    CAS  PubMed  Article  Google Scholar 

  118. 118.

    Fernandez, F. et al. Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome. Nat. Neurosci. 10, 411–413 (2007).

    CAS  PubMed  Article  Google Scholar 

  119. 119.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. 120.

    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).

    PubMed  Article  Google Scholar 

  121. 121.

    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).

    PubMed  PubMed Central  Article  Google Scholar 

  122. 122.

    Centonze, D. et al. Abnormal striatal GABA transmission in the mouse model for the fragile X syndrome. Biol. Psychiatry 63, 963–973 (2008).

    CAS  PubMed  Article  Google Scholar 

  123. 123.

    Egawa, K. et al. Decreased tonic inhibition in cerebellar granule cells causes motor dysfunction in a mouse model of Angelman syndrome. Sci. Transl. Med. 4, 163ra157 (2012).

    PubMed  Article  CAS  Google Scholar 

  124. 124.

    Sivilia, S. et al. CDKL5 knockout leads to altered inhibitory transmission in the cerebellum of adult mice. Genes Brain Behav. 15, 491–502 (2016).

    CAS  PubMed  Article  Google Scholar 

  125. 125.

    Rein, B. et al. Reversal of synaptic and behavioral deficits in a 16p11.2 duplication mouse model via restoration of the GABA synapse regulator Npas4. Mol. Psychiatry https://doi.org/10.1038/s41380-020-0693-9 (2020).

    Article  PubMed  Google Scholar 

  126. 126.

    Hubner, C. A. et al. Disruption of KCC2 reveals an essential role of K-Cl cotransport already in early synaptic inhibition. Neuron 30, 515–524 (2001). This study shows that knocking out Slc12a5 in mice causes severe motor and respiration deficits and is incompatible with life, demonstrating the importance of KCC2 and GABAergic inhibition in the proper development and functioning of the nervous system.

    CAS  PubMed  Article  Google Scholar 

  127. 127.

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

    CAS  Article  Google Scholar 

  128. 128.

    Wang, P. et al. CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in neurodevelopment. Mol. Autism. 6, 55 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  129. 129.

    Talos, D. M. et al. Altered inhibition in tuberous sclerosis and type IIb cortical dysplasia. Ann. Neurol. 71, 539–551 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  130. 130.

    Robertson, C. E., Ratai, E. M. & Kanwisher, N. Reduced GABAergic action in the autistic brain. Curr. Biol. 26, 80–85 (2016).

    CAS  PubMed  Article  Google Scholar 

  131. 131.

    Port, R. G. et al. Exploring the relationship between cortical GABA concentrations, auditory gamma-band responses and development in ASD: evidence for an altered maturational trajectory in ASD. Autism Res. 10, 593–607 (2017).

    PubMed  Article  Google Scholar 

  132. 132.

    Bruining, H. et al. Measurement of excitation–inhibition ratio in autism spectrum disorder using critical brain dynamics. Sci. Rep. 10, 9195 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  133. 133.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. 134.

    Hashemi, E., Ariza, J., Rogers, H., Noctor, S. C. & Martinez-Cerdeno, V. The number of parvalbumin-expressing interneurons is decreased in the prefrontal cortex in autism. Cereb. Cortex 27, 1931–1943 (2017).

    PubMed  Google Scholar 

  135. 135.

    Penagarikano, O. et al. Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits. Cell 147, 235–246 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  136. 136.

    Filice, F., Vorckel, K. J., Sungur, A. O., Wohr, M. & Schwaller, B. Reduction in parvalbumin expression not loss of the parvalbumin-expressing GABA interneuron subpopulation in genetic parvalbumin and shank mouse models of autism. Mol. Brain 9, 10 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  137. 137.

    Gogolla, N. et al. Common circuit defect of excitatory–inhibitory balance in mouse models of autism. J. Neurodev. Disord. 1, 172–181 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  138. 138.

    Jung, E. M. et al. Arid1b haploinsufficiency disrupts cortical interneuron development and mouse behavior. Nat. Neurosci. 20, 1694–1707 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  139. 139.

    Vogt, D., Cho, K. K. A., Lee, A. T., Sohal, V. S. & Rubenstein, J. L. R. The parvalbumin/somatostatin ratio is increased in Pten mutant mice and by human PTEN ASD alleles. Cell Rep. 11, 944–956 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  140. 140.

    Lauber, E., Filice, F. & Schwaller, B. Prenatal valproate exposure differentially affects parvalbumin-expressing neurons and related circuits in the cortex and striatum of mice. Front. Mol. Neurosci. 9, 150 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  141. 141.

    Perez-Cremades, D. et al. Alteration of inhibitory circuits in the somatosensory cortex of Ts65Dn mice, a model for Down’s syndrome. J. Neural Transm. 117, 445–455 (2010).

    CAS  PubMed  Article  Google Scholar 

  142. 142.

    Stoner, R. et al. Patches of disorganization in the neocortex of children with autism. N. Engl. J. Med. 370, 1209–1219 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  143. 143.

    Yu, F. H. et al. Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy. Nat. Neurosci. 9, 1142–1149 (2006).

    CAS  PubMed  Article  Google Scholar 

  144. 144.

    Cheah, C. S. et al. Specific deletion of NaV1.1 sodium channels in inhibitory interneurons causes seizures and premature death in a mouse model of Dravet syndrome. Proc. Natl Acad. Sci. USA 109, 14646–14651 (2012).

    CAS  PubMed  Article  Google Scholar 

  145. 145.

    Spratt, P. W. E. et al. The autism-associated gene Scn2a contributes to dendritic excitability and synaptic function in the prefrontal cortex. Neuron 103, 673–685 e675 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  146. 146.

    Ogiwara, I. et al. Nav1.2 haplodeficiency in excitatory neurons causes absence-like seizures in mice. Commun. Biol. 1, 96 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  147. 147.

    Yuan, Y. et al. Delayed maturation of GABAergic signaling in the Scn1a and Scn1b mouse models of Dravet Syndrome. Sci. Rep. 9, 6210 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  148. 148.

    Torrico, B. et al. Contribution of common and rare variants of the PTCHD1 gene to autism spectrum disorders and intellectual disability. Eur. J. Hum. Genet. 23, 1694–1701 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  149. 149.

    Wells, M. F., Wimmer, R. D., Schmitt, L. I., Feng, G. & Halassa, M. M. Thalamic reticular impairment underlies attention deficit in Ptchd1Y/– mice. Nature 532, 58–63 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  150. 150.

    Sun, Y. G. et al. GABAergic synaptic transmission triggers action potentials in thalamic reticular nucleus neurons. J. Neurosci. 32, 7782–7790 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  151. 151.

    Goldman, S. E. et al. Defining the sleep phenotype in children with autism. Dev. Neuropsychol. 34, 560–573 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  152. 152.

    Young, D. et al. Sleep problems in Rett syndrome. Brain Dev. 29, 609–616 (2007).

    PubMed  PubMed Central  Article  Google Scholar 

  153. 153.

    Han, S. et al. NaV1.1 channels are critical for intercellular communication in the suprachiasmatic nucleus and for normal circadian rhythms. Proc. Natl Acad. Sci. USA 109, E368–E377 (2012).

    CAS  PubMed  Article  Google Scholar 

  154. 154.

    Fenno, L. E. et al. Comprehensive dual- and triple-feature intersectional single-vector delivery of diverse functional payloads to cells of behaving mammals. Neuron 107, 836–853 (2020).

    CAS  PubMed  Article  Google Scholar 

  155. 155.

    Chao, H. T. et al. Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes. Nature 468, 263–269 (2010). This study demonstrates that knocking out the Mecp2 gene specifically in GABAergic neurons in the mouse brain partially recapitulates Rett syndrome phenotypes as observed in global Mecp2-knockout mice, suggesting the contribution of GABAergic inhibition deficits in the pathogenesis of Rett syndrome.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  156. 156.

    Ure, K. et al. Restoration of Mecp2 expression in GABAergic neurons is sufficient to rescue multiple disease features in a mouse model of Rett syndrome. Elife 5, e14198 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  157. 157.

    Judson, M. C. et al. GABAergic neuron-specific loss of Ube3a causes Angelman syndrome-like EEG abnormalities and enhances seizure susceptibility. Neuron 90, 56–69 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  158. 158.

    Yoo, T. et al. GABA neuronal deletion of Shank3 exons 14-16 in mice suppresses striatal excitatory synaptic input and induces social and locomotor abnormalities. Front. Cell Neurosci. 12, 341 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  159. 159.

    Rudolph, S. et al. Cerebellum-specific deletion of the GABAA receptor δ subunit leads to sex-specific disruption of behavior. Cell Rep. 33, 108338 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  160. 160.

    Yizhar, O. et al. Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature 477, 171–178 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  161. 161.

    Hong, W., Kim, D. W. & Anderson, D. J. Antagonistic control of social versus repetitive self-grooming behaviors by separable amygdala neuronal subsets. Cell 158, 1348–1361 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  162. 162.

    Tropea, D. et al. Partial reversal of Rett syndrome-like symptoms in MeCP2 mutant mice. Proc. Natl Acad. Sci. USA 106, 2029–2034 (2009).

    CAS  PubMed  Article  Google Scholar 

  163. 163.

    Sato, M. & Stryker, M. P. Genomic imprinting of experience-dependent cortical plasticity by the ubiquitin ligase gene Ube3a. Proc. Natl Acad. Sci. USA 107, 5611–5616 (2010).

    CAS  PubMed  Article  Google Scholar 

  164. 164.

    Harlow, E. G. et al. Critical period plasticity is disrupted in the barrel cortex of Fmr1 knockout mice. Neuron 65, 385–398 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  165. 165.

    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).

    CAS  PubMed  Article  Google Scholar 

  166. 166.

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  167. 167.

    Tatavarty, V. et al. Autism-associated Shank3 is essential for homeostatic compensation in rodent V1. Neuron 106, 769–777 e764 (2020).

    CAS  PubMed  Article  Google Scholar 

  168. 168.

    Sinclair, D., Oranje, B., Razak, K. A., Siegel, S. J. & Schmid, S. Sensory processing in autism spectrum disorders and fragile X syndrome — from the clinic to animal models. Neurosci. Biobehav. Rev. 76, 235–253 (2017).

    CAS  PubMed  Article  Google Scholar 

  169. 169.

    Modi, M. E. & Sahin, M. Translational use of event-related potentials to assess circuit integrity in ASD. Nat. Rev. Neurol. 13, 160–170 (2017).

    CAS  PubMed  Article  Google Scholar 

  170. 170.

    Antoine, M. W., Langberg, T., Schnepel, P. & Feldman, D. E. Increased excitation–inhibition ratio stabilizes synapse and circuit excitability in four autism mouse models. Neuron 101, 648–661 e644 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  171. 171.

    Guy, J., Gan, J., Selfridge, J., Cobb, S. & Bird, A. Reversal of neurological defects in a mouse model of Rett syndrome. Science 315, 1143–1147 (2007).

    CAS  PubMed  Article  Google Scholar 

  172. 172.

    Mei, Y. et al. Adult restoration of Shank3 expression rescues selective autistic-like phenotypes. Nature 530, 481–484 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  173. 173.

    Zeier, Z. et al. Fragile X mental retardation protein replacement restores hippocampal synaptic function in a mouse model of fragile X syndrome. Gene Ther. 16, 1122–1129 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  174. 174.

    Garg, S. K. et al. Systemic delivery of MeCP2 rescues behavioral and cellular deficits in female mouse models of Rett syndrome. J. Neurosci. 33, 13612–13620 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  175. 175.

    US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT03872479 (2019).

  176. 176.

    Hilton, I. B. et al. Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers. Nat. Biotechnol. 33, 510–517 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  177. 177.

    Liu, X. S. et al. Editing DNA methylation in the mammalian genome. Cell 167, 233–247 e217 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  178. 178.

    Qin, L. et al. Social deficits in Shank3-deficient mouse models of autism are rescued by histone deacetylase (HDAC) inhibition. Nat. Neurosci. 21, 564–575 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  179. 179.

    An, D. et al. Systemic messenger RNA therapy as a treatment for methylmalonic acidemia. Cell Rep. 21, 3548–3558 (2017).

    CAS  PubMed  Article  Google Scholar 

  180. 180.

    Pratt, A. J. & MacRae, I. J. The RNA-induced silencing complex: a versatile gene-silencing machine. J. Biol. Chem. 284, 17897–17901 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  181. 181.

    Sztainberg, Y. et al. Reversal of phenotypes in MECP2 duplication mice using genetic rescue or antisense oligonucleotides. Nature 528, 123–126 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  182. 182.

    Kim, J. et al. Patient-customized oligonucleotide therapy for a rare genetic disease. N. Engl. J. Med. 381, 1644–1652 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  183. 183.

    Griffin, C. E. 3rd, Kaye, A. M., Bueno, F. R. & Kaye, A. D. Benzodiazepine pharmacology and central nervous system-mediated effects. Ochsner J. 13, 214–223 (2013).

    PubMed  PubMed Central  Google Scholar 

  184. 184.

    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).

    PubMed  Article  CAS  Google Scholar 

  185. 185.

    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).

    CAS  PubMed  Article  Google Scholar 

  186. 186.

    Berry-Kravis, E. M. et al. Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome. Nat. Rev. Drug Discov. 17, 280–299 (2018).

    CAS  PubMed  Article  Google Scholar 

  187. 187.

    Kharod, S. C., Kang, S. K. & Kadam, S. D. Off-label use of bumetanide for brain disorders: an overview. Front. Neurosci. 13, 310 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  188. 188.

    Delpire, E. et al. Further optimization of the K-Cl cotransporter KCC2 antagonist ML077: development of a highly selective and more potent in vitro probe. Bioorg Med. Chem. Lett. 22, 4532–4535 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  189. 189.

    Gagnon, M. et al. Chloride extrusion enhancers as novel therapeutics for neurological diseases. Nat. Med. 19, 1524–1528 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  190. 190.

    Cardarelli, R. A. et al. The small molecule CLP257 does not modify activity of the K+-Cl co-transporter KCC2 but does potentiate GABAA receptor activity. Nat. Med. 23, 1394–1396 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  191. 191.

    Gagnon, M. et al. Reply to the small molecule CLP257 does not modify activity of the K+-Cl co-transporter KCC2 but does potentiate GABAA receptor activity. Nat. Med. 23, 1396–1398 (2017).

    CAS  PubMed  Article  Google Scholar 

  192. 192.

    de Los Heros et al. The WNK-regulated SPAK/OSR1 kinases directly phosphorylate and inhibit the K+-Cl co-transporters. Biochem. J. 458, 559–573 (2014).

    PubMed  Article  CAS  Google Scholar 

  193. 193.

    Kahle, K. T., Rinehart, J. & Lifton, R. P. Phosphoregulation of the Na-K-2Cl and K-Cl cotransporters by the WNK kinases. Biochim. Biophys. Acta 1802, 1150–1158 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  194. 194.

    Moore, Y. E., Deeb, T. Z., Chadchankar, H., Brandon, N. J. & Moss, S. J. Potentiating KCC2 activity is sufficient to limit the onset and severity of seizures. Proc. Natl Acad. Sci. USA 115, 10166–10171 (2018).

    CAS  PubMed  Article  Google Scholar 

  195. 195.

    McCamphill, P. K. et al. Selective inhibition of glycogen synthase kinase 3α corrects pathophysiology in a mouse model of fragile X syndrome. Sci. Transl. Med. 12, eaam8572 (2020).

    CAS  PubMed  Article  Google Scholar 

  196. 196.

    O’Leary, H. M. et al. Placebo-controlled crossover assessment of mecasermin for the treatment of Rett syndrome. Ann. Clin. Transl. Neurol. 5, 323–332 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  197. 197.

    Vahdatpour, C., Dyer, A. H. & Tropea, D. Insulin-like growth factor 1 and related compounds in the treatment of childhood-onset neurodevelopmental disorders. Front. Neurosci. 10, 450 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  198. 198.

    Glaze, D. G. et al. Double-blind, randomized, placebo-controlled study of trofinetide in pediatric Rett syndrome. Neurology 92, e1912–e1925 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  199. 199.

    Hnisz, D., Shrinivas, K., Young, R. A., Chakraborty, A. K. & Sharp, P. A. A phase separation model for transcriptional control. Cell 169, 13–23 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  200. 200.

    Feng, Z., Chen, X., Zeng, M. & Zhang, M. Phase separation as a mechanism for assembling dynamic postsynaptic density signalling complexes. Curr. Opin. Neurobiol. 57, 1–8 (2019).

    CAS  PubMed  Article  Google Scholar 

  201. 201.

    Lai, A., Valdez-Sinon, A. N. & Bassell, G. J. Regulation of RNA granules by FMRP and implications for neurological diseases. Traffic 21, 454–462 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  202. 202.

    Zeng, M. et al. Reconstituted postsynaptic density as a molecular platform for understanding synapse formation and plasticity. Cell 174, 1172–1187 e1116 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  203. 203.

    Rapanelli, M. et al. Behavioral, circuitry, and molecular aberrations by region-specific deficiency of the high-risk autism gene Cul3. Mol. Psychiatry https://doi.org/10.1038/s41380-019-0498-x (2019).

    Article  PubMed  Google Scholar 

  204. 204.

    Lu, J. et al. Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4. Chem. Biol. 22, 755–763 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  205. 205.

    Delpire, E. & Weaver, C. D. Challenges of finding novel drugs targeting the K-Cl cotransporter. ACS Chem. Neurosci. 7, 1624–1627 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  206. 206.

    Tang, X. et al. Pharmacological enhancement of KCC2 gene expression exerts therapeutic effects on human Rett syndrome neurons and Mecp2 mutant mice. Sci. Transl. Med. 11, eaau0164 (2019). This study reports the discovery of the first group of small-molecule compounds that enhance KCC2 gene expression using human neuron and mouse models of Rett syndrome to demonstrate the therapeutic efficacy of identified compounds in rescuing neural circuit and behaviour phenotypes.

    PubMed  Article  CAS  Google Scholar 

  207. 207.

    Han, S. et al. Autistic-like behaviour in Scn1a+/– mice and rescue by enhanced GABA-mediated neurotransmission. Nature 489, 385–390 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  208. 208.

    Han, S., Tai, C., Jones, C. J., Scheuer, T. & Catterall, W. A. Enhancement of inhibitory neurotransmission by GABAA receptors having α2,3-subunits ameliorates behavioral deficits in a mouse model of autism. Neuron 81, 1282–1289 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  209. 209.

    Lemonnier, E. et al. A randomised controlled trial of bumetanide in the treatment of autism in children. Transl. Psychiatry 2, e202 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  210. 210.

    Lemonnier, E. et al. Treating fragile X syndrome with the diuretic bumetanide: a case report. Acta Paediatr. 102, e288–e290 (2013).

    PubMed  Article  Google Scholar 

  211. 211.

    Sprengers, J. J. et al. Bumetanide for core symptoms of autism spectrum disorder (BAMBI): a single center, double-blinded, participant-randomized, placebo-controlled, phase-2 superiority trial. J. Am. Acad. Child Adolesc. Psychiatry S0890-8567, 31290–31299 (2020).

    Google Scholar 

  212. 212.

    Castrop, H. & Schiessl, I. M. Physiology and pathophysiology of the renal Na-K-2Cl cotransporter (NKCC2). Am. J. Physiol. Ren. Physiol. 307, F991–F1002 (2014).

    CAS  Article  Google Scholar 

  213. 213.

    Williams, J. R., Sharp, J. W., Kumari, V. G., Wilson, M. & Payne, J. A. The neuron-specific K-Cl cotransporter, KCC2. Antibody development and initial characterization of the protein. J. Biol. Chem. 274, 12656–12664 (1999).

    CAS  PubMed  Article  Google Scholar 

  214. 214.

    Chen, B. et al. Reactivation of dormant relay pathways in injured spinal cord by KCC2 manipulations. Cell 174, 1599 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  215. 215.

    Takayanagi, Y. et al. Pervasive social deficits, but normal parturition, in oxytocin receptor-deficient mice. Proc. Natl Acad. Sci. USA 102, 16096–16101 (2005).

    CAS  PubMed  Article  Google Scholar 

  216. 216.

    Leonzino, M. et al. The timing of the excitatory-to-inhibitory GABA switch is regulated by the oxytocin receptor via KCC2. Cell Rep. 15, 96–103 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  217. 217.

    Tyzio, R. et al. Maternal oxytocin triggers a transient inhibitory switch in GABA signaling in the fetal brain during delivery. Science 314, 1788–1792 (2006).

    CAS  PubMed  Article  Google Scholar 

  218. 218.

    Andari, E. et al. Promoting social behavior with oxytocin in high-functioning autism spectrum disorders. Proc. Natl Acad. Sci. USA 107, 4389–4394 (2010).

    CAS  PubMed  Article  Google Scholar 

  219. 219.

    Yatawara, C. J., Einfeld, S. L., Hickie, I. B., Davenport, T. A. & Guastella, A. J. The effect of oxytocin nasal spray on social interaction deficits observed in young children with autism: a randomized clinical crossover trial. Mol. Psychiatry 21, 1225–1231 (2016).

    CAS  PubMed  Article  Google Scholar 

  220. 220.

    Xiao, L., Priest, M. F., Nasenbeny, J., Lu, T. & Kozorovitskiy, Y. Biased oxytocinergic modulation of midbrain dopamine systems. Neuron 95, 368–384 e365 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  221. 221.

    Sgritta, M. et al. Mechanisms underlying microbial-mediated changes in social behavior in mouse models of autism spectrum disorder. Neuron 101, 246–259 e246 (2019).

    CAS  PubMed  Article  Google Scholar 

  222. 222.

    Buffington, S. A. et al. Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring. Cell 165, 1762–1775 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  223. 223.

    Gong, X. et al. An ultra-sensitive step-function opsin for minimally invasive optogenetic stimulation in mice and macaques. Neuron 107, 38–51.e8 (2020).

    CAS  PubMed  Article  Google Scholar 

  224. 224.

    Wang, W. et al. Chemogenetic activation of prefrontal cortex rescues synaptic and behavioral deficits in a mouse model of 16p11.2 deletion syndrome. J. Neurosci. 38, 5939–5948 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  225. 225.

    Qin, L., Ma, K. & Yan, Z. Chemogenetic activation of prefrontal cortex in Shank3-deficient mice ameliorates social deficits, NMDAR hypofunction, and Sgk2 downregulation. iScience 17, 24–35 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  226. 226.

    Larimer, P., Spatazza, J., Stryker, M. P., Alvarez-Buylla, A. & Hasenstaub, A. R. Development and long-term integration of MGE-lineage cortical interneurons in the heterochronic environment. J. Neurophysiol. 118, 131–139 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  227. 227.

    Hunt, R. F., Girskis, K. M., Rubenstein, J. L., Alvarez-Buylla, A. & Baraban, S. C. GABA progenitors grafted into the adult epileptic brain control seizures and abnormal behavior. Nat. Neurosci. 16, 692–697 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  228. 228.

    Martinez-Losa, M. et al. Nav1.1-overexpressing interneuron transplants restore brain rhythms and cognition in a mouse model of Alzheimer’s disease. Neuron 98, 75–89 e75 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  229. 229.

    Brock, J., Brown, C. C., Boucher, J. & Rippon, G. The temporal binding deficit hypothesis of autism. Dev. Psychopathol. 14, 209–224 (2002).

    PubMed  Article  Google Scholar 

  230. 230.

    Chiken, S. & Nambu, A. High-frequency pallidal stimulation disrupts information flow through the pallidum by GABAergic inhibition. J. Neurosci. 33, 2268–2280 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  231. 231.

    Hao, S. et al. Forniceal deep brain stimulation rescues hippocampal memory in Rett syndrome mice. Nature 526, 430–434 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

This work was funded by a Bridge to Independence Award from the Simons Foundation Autism Research Initiative awarded to X.T., US National Institutes of Health (NIH) grant R01 MH104610 awarded to R.J., and NIH grant R01 MH085802 and a grant to the Simons Center for the Social Brain from the Simons Foundation Autism Research Initiative awarded to M.S. The authors also thank C. Clairmont for his substantial help with revising the manuscript, and X. Jing, M. Enriquez, K. Cruite, M. Gallagher, D. Tomasello, E. Wogram and E. Majercak for useful comments and discussions.

Author information

Affiliations

Authors

Contributions

X.T. researched data for the article. All authors contributed equally to discussion of content, writing and reviewing or editing of the manuscript.

Corresponding author

Correspondence to Xin Tang.

Ethics declarations

Competing interests

R.J. is a cofounder of Fate Therapeutics, Fulcrum Therapeutics and Omega Therapeutics.

Additional information

Peer review information

Nature Reviews Neuroscience thanks A. Contractor, V. Martínez Cerdeño, Z. Yan and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

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

Glossary

NDD risk genes

Candidate genes identified from patient populations with clinically diagnosed neurodevelopmental disorders (NDDs) in which mutations are associated with increased risk of developing NDD symptoms.

Transcription factors

Proteins that bind to specific DNA sequence motifs and regulate the transcriptional levels of target genes to determine cellular identity and function.

Excitation–inhibition (E/I) imbalance

Disruption in the balance between excitatory and inhibitory drives that causes either overexcitation or underexcitation of neural circuits observed in various neurodevelopmental disorder subtypes.

Stratification of patients

Rational partitioning of patients into subgroups, based on their behavioural metrics, biomarkers and genetic information, to facilitate precise diagnosis and targeted treatment.

Precision medicine

An approach to medicine that considers the biological variabilities of each patient, such as sex, genetics and other biomarkers, for devising personalized treatment regimens.

Epigenetic factors

Modifications to the chromosome, including methylation and histone modifications, that regulate the expression level of genes without altering the primary DNA sequence.

GABA functional switch

A developmental process during which GABA action switches from excitatory to inhibitory, driven mainly by altered expression and function of the chloride transporters NKCC1 and KCC2.

Homeostatic mechanism

Regulatory feedback signals involving changes in synapse number, synaptic strength and GABA signalling efficacy that stabilize neuronal and neural network excitability and function.

Martinotti cells

Small multipolar interneurons, with short branching dendrites, that send projections to layer 1 and provide dendritic inhibition mainly for layer 5 pyramidal neurons to facilitate feedback inhibition.

Critical period

A developmental stage often perturbed in neurodevelopmental disorders, and during which the connectivity of the nervous system is especially susceptible to long-term alterations by environmental stimuli.

Ocular dominance plasticity

Changes in relative responses of visual cortex neurons to stimulation of the two eyes due to visual deprivation. This plasticity is triggered by changes in GABAergic inhibition.

X-linked intellectual disability

A subset of male-biased intellectual disability cases that are associated with inheritance of mutant genes on the X chromosome.

Somatic mosaic mutations

Genetic mutations that are absent in the zygote stage but present only in the progeny of mutant cells that occur during the developmental process.

Chromatin looping

Dynamic process in which multiple distal genomic regions are brought into proximity through DNA–protein interactions to provide a structural basis for long-range gene transcription regulation.

Syndromic forms of NDD

A clinical classification of neurodevelopmental disorder (NDD) characterized by patterned neurobehavioural phenotypes and defined genetic causes, including chromosomal aberrations, copy number variations and single gene mutations.

Binocular rivalry

A visual phenomenon regulated by GABAergic inhibition in which different images presented to each eye compete for awareness, resulting in alternating perception.

Transcription activator-like effector nucleases

(TALENs). Artificial DNases engineered through fusing a transcription activator-like effector DNA-binding domain to a DNA cleavage domain for the purpose of cutting and editing specific DNA sequences.

Proteolysis-targeting chimeras

(PROTACs) Engineered small molecules composed of two distinct domain classes: one that engages E3 ubiquitin ligase and the other that binds to target proteins for degradation.

Autism Diagnostic Observation Schedule

A standardized assessment tool that clinicians may use for diagnosing autism spectrum disorder in patients through the use of semistructured play or interview sessions.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tang, X., Jaenisch, R. & Sur, M. The role of GABAergic signalling in neurodevelopmental disorders. Nat Rev Neurosci 22, 290–307 (2021). https://doi.org/10.1038/s41583-021-00443-x

Download citation

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