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Excitation-inhibition balance as a framework for investigating mechanisms in neuropsychiatric disorders

Molecular Psychiatry volume 24, pages 1248–1257 (2019)Cite this article

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Abstract

In 2003 Rubenstein and Merzenich hypothesized that some forms of Autism (ASD) might be caused by a reduction in signal-to-noise in key neural circuits, which could be the result of changes in excitatory-inhibitory (E-I) balance. Here, we have clarified the concept of E-I balance, and updated the original hypothesis in light of the field’s increasingly sophisticated understanding of neuronal circuits. We discuss how specific developmental mechanisms, which reduce inhibition, affect cortical and hippocampal functions. After describing how mutations of some ASD genes disrupt inhibition in mice, we close by suggesting that E-I balance represents an organizing framework for understanding findings related to pathophysiology and for identifying appropriate treatments.

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References

  1. Rubenstein JLR, Merzenich MM. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav. 2003;2:255–67.

    Article  CAS  PubMed  Google Scholar 

  2. Lee E, Lee J, Kim E. Excitation/Inhibition imbalance in animal models of autism spectrum disorders. Biol Psychiatry. 2017;81:838–47.

    Article  PubMed  Google Scholar 

  3. Bourgeron T. From the genetic architecture to synaptic plasticity in autism spectrum disorder. Nat Rev Neurosci. 2015;16:551–63.

    Article  CAS  PubMed  Google Scholar 

  4. Geschwind DH, Levitt P. Autism spectrum disorders: developmental disconnection syndromes. Curr Opin Neurobiol. 2007;17:103–11.

    Article  CAS  PubMed  Google Scholar 

  5. Mullins C, Fishell G, Tsien RW. Unifying views of autism spectrum disorders: a consideration of autoregulatory feedback loops. Neuron. 2016;89:1131–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Nelson SB, Valakh V. Excitatory/inhibitory balance and circuit homeostasis in autism spectrum disorders. Neuron. 2015;87:684–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ramocki MB, Zoghbi HY. Failure of neuronal homeostasis results in common neuropsychiatric phenotypes. Nature. 2008;455:912–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Rubenstein JLR. Three hypotheses for developmental defects that may underlie some forms of autism. Curr Opin Neurol. 2010;23:118–23.

    Article  PubMed  Google Scholar 

  9. Toro R, Konyukh M, Delorme R, Leblond C, Chaste P, Fauchereau F, et al. Key role for gene dosage and synaptic homeostasis in autism spectrum disorders. Trends Genet. 2010;26:363–72.

    Article  CAS  PubMed  Google Scholar 

  10. Wondolowski J, Dickman D. Emerging links between homeostatic synaptic plasticity and neurological disease. Front Cell Neurosci. 2016;7:223.

    Google Scholar 

  11. Canitano R, Pallagrosi M. Autism spectrum disorders and schizophrenia spectrum disorders: excitation/inhibition imbalance and developmental trajectories. Front Psychiatry. 2017;8:69.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Ebert DH, Greenberg ME. Activity-dependent neuronal signalling and autism spectrum disorder. Nature. 2013;493:327–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Darnell JC, Klann E. The translation of translational control by FMRP: therapeutic targets for FXS. Nat Neurosci. 2013;16:1530–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kelleher RJ 3rd, Bear MF. The autistic neuron: troubled translation? Cell. 2008;135:401–6.

    Article  CAS  PubMed  Google Scholar 

  15. Iascone DM, Li Y, Sümbül U, Doron M, Chen H, Andreu V, et al. Principles of excitatory and inhibitory synaptic organization constrain dendritic spiking in pyramidal neurons. BioRxiv. 2018. https://doi.org/10.1101/395384.

  16. Hengen KB, Lambo ME, Van Hooser SD, Katz DB, Turrigiano GG. Firing rate homeostasis in visual cortex of freely behaving rodents. Neuron. 2013;80:335–42.

    Article  CAS  PubMed  Google Scholar 

  17. Adesnik H, Scanziani M. Lateral competition for cortical space by layer-specific horizontal circuits. Nature. 2010;464:1155–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yizhar O, Fenno LE, Prigge M, Schneider F, Davidson TJ, O’Shea DJ, et al. Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature. 2011;477:171–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Shew WL, Yang H, Yu S, Roy R, Plenz D. Information capacity and transmission are maximized in balanced cortical networks with neuronal avalanches. J Neurosci. 2011;31:55–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Haider B, Duque A, Hasenstaub AR, McCormick DA. Neocortical network activity in vivo is generated through a dynamic balance of excitation and inhibition. J Neurosci. 2006;26:4535–45.

    Article  CAS  PubMed  Google Scholar 

  21. Sanchez-Vives MV, McCormick DA. Cellular and network mechanisms of rhythmic recurrent activity in neocortex. Nat Neurosci. 2000;3:1027–34.

    Article  CAS  PubMed  Google Scholar 

  22. Litwin-Kumar A, Doiron B. Slow dynamics and high variability in balanced cortical networks with clustered connections. Nat Neurosci. 2012;15:1498–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lee AT, Gee SM, Vogt D, Patel T, Rubenstein JL, Sohal VS. Pyramidal neurons in prefrontal cortex receive subtype-specific forms of excitation and inhibition. Neuron. 2014a;81:61–68.

    Article  CAS  PubMed  Google Scholar 

  24. Lee SH, Marchionni I, Bezaire M, Varga C, Danielson N, Lovett-Barron M, et al. Parvalbumin-positive basket cells differentiate among hippocampal pyramidal cells. Neuron. 2014b;82:1129–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hasenstaub A, Sachdev RN, McCormick DA. State changes rapidly modulate cortical neuronal responsiveness. J Neurosci. 2007;27:9607–22.

    Article  CAS  PubMed  Google Scholar 

  26. Lu J, Tucciarone J, Padilla-Coreano N, He M, Gordon JA, Huang ZJ. Selective inhibitory control of pyramidal neuron ensembles and cortical subnetworks by chandelier cells. Nat Neurosci. 2017;20:1377–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lee S, Kruglikov I, Huang ZJ, Fishell G, Rudy B. A disinhibitory circuit mediates motor integration in the somatosensory cortex. Nat Neurosci. 2013;16:1662–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Pi HJ, Hangya B, Kvitsiani D, Sanders JI, Huang ZJ, Kepecs A. Cortical interneurons that specialize in disinhibitory control. Nature. 2013;503:521–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Pfeffer CK, Xue M, He M, Huang ZJ, Scanziani M. Inhibition of inhibition in visual cortex: the logic of connections between molecularly distinct interneurons. Nat Neurosci. 2013;16:1068–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Chu J, Anderson SA. Development of cortical interneurons. Neuropsychopharmacology. 2015;40:16–23.

    Article  PubMed  Google Scholar 

  31. Wamsley B, Fishell G. Genetic and activity-dependent mechanisms underlying interneuron diversity. Nat Rev Neurosci. 2017;18:299–309.

    Article  CAS  PubMed  Google Scholar 

  32. Lim L, Mi D, Llorca A, Marín O. Development and functional diversification of cortical interneurons. Neuron. 2018;100:294–313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hu JS, Vogt D, Sandberg M, Rubenstein JL. Cortical interneuron development: a tale of time and space. Development. 2017;144:3867–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Panganiban G, Rubenstein JLR. Developmental functions of the Distal-less (Dlx) homeobox genes. Development. 2002;129:4371–86.

    CAS  PubMed  Google Scholar 

  35. Colasante G, Patrick Collombat P, Raimondi V, Bonanomi D, Ferrai C, Maira M, et al. Arx is a direct target of Dlx2 and thereby contributes to the tangential migration of GABAergic interneurons. J Neurosci. 2008;28:10674–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. McKinsey GL, Lindtner S, Trzcinski B, Visel A, Pennacchio L, Huylebroeck D, et al. Dlx1&2-dependent expression of Zfhx1b (Sip1, Zeb2) regulates the fate switch between cortical and striatal interneurons. Neuron. 2013;77:83–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Pla R, Stanco A, Howard MA, Vogt D, Rubin A, Mortimer N, et al. Dlx1/2 promote interneuron GABA synthesis, synaptogenesis, and dendritogenesis through Grin2b. Cereb Cortex. 2017;28:1–19.

    Google Scholar 

  38. Anderson SA, Eisenstat D, Shi L, Rubenstein JLR. Interneuron migration from basal forebrain:dependence on Dlx genes. Science. 1997a;278:474–6.

    Article  CAS  PubMed  Google Scholar 

  39. Anderson S, Qiu M, Bulfone A, Eisenstat D, Meneses JJ, Pedersen RA, et al. Mutations of the homeobox genes Dlx-1 and Dlx-2 disrupt the striatal subventricular zone and differentiation of late-born striatal cells. Neuron. 1997b;19:27–37.

    Article  CAS  PubMed  Google Scholar 

  40. Long JE, Garel S, Alvarez-Dolado M, Yoshikawa K, Osumi N, Alvarez-Buylla A, et al. Dlx-dependent and independent regulation of olfactory bulb interneuron differentiation. J Neurosci. 2007;27:3230–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Long JE, Swan C, Liang WS, Cobos I, Potter GB, Rubenstein JLR. Dlx1&2 and Mash1 transcription factors control striatal patterning and differentiation through parallel and overlapping pathways. J Comp Neurol. 2009;512:556–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Le TN, Zhou QP, Cobos I, Zhang S, Zagozewski J, Japoni S, et al. GABAergic interneuron differentiation in the basal forebrain is mediated through direct regulation of glutamic acid decarboxylase isoforms by Dlx homeobox transcription factors. J Neurosci. 2017;37:8816–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Cobos I, Calcagnotto ME, Vilaythong AJ, Noebels J, Baraban SC, Rubenstein JLR. Mice lacking the Dlx1 transcription factor exhibit subtype-specific loss of interneurons, reduced synaptic inhibition and epilepsy. Nature Neurosci. 2005;8:1059–68.

    Article  CAS  PubMed  Google Scholar 

  44. Miyoshi G, Young A, Petros T, Karayannis T, McKenzie Chang M, Lavado A, et al. Prox1 regulates the subtype-specific development of caudal ganglionic eminence-derived GABAergic cortical interneurons. J Neurosci. 2015;35:12869–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Karayannis T, Au E, Patel JC, Kruglikov I, Markx S, Delorme R, et al. Cntnap4 differentially contributes to GABAergic and dopaminergic synaptic transmission. Nature. 2014;511:236–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Del Pino I, Brotons-Mas JR, Marques-Smith A, Marighetto A, Frick A, Marín O, et al. Abnormal wiring of CCK+ basket cells disrupts spatial information coding. Nat Neurosci. 2017;20:784–92.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Howard MA, Rubenstein JL, Baraban SC. Bidirectional homeostatic plasticity induced by interneuron cell death and transplantation in vivo. Proc Natl Acad Sci USA. 2014;111:492–7.

    Article  CAS  PubMed  Google Scholar 

  48. Jones D, Howard M, Stanco A, Rubenstein JLR, Baraban S. Deletion of Dlx1 results in reduced glutamatergic input to hippocampal interneurons. J Neurophys. 2011;105:1984–91.

    Article  Google Scholar 

  49. Mao R, Schummers J, Knoblich U, Lacey CJ, Van Wart A, Cobos I, et al. Influence of a subtype of inhibitory interneuron on stimulus-specific responses in visual cortex. Cereb Cortex. 2012;22:493–508.

    Article  PubMed  Google Scholar 

  50. Seybold BA, Stanco A, Cho K, Potter G, Kim C, Sohal V, et al. Chronic reduction in inhibition reduces receptive field size in mouse auditory cortex. PNAS. 2012;109:13829–34.

    Article  CAS  PubMed  Google Scholar 

  51. Wang Y, Dye C, Sohal V, Long J, Estrada R, Roztocil T, et al. Dlx5 and Dlx6 regulate the development of parvalbumin-expressing cortical interneurons. J Neurosci. 2010;30:5334–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Selimbeyoglu A, Kim CK, Inoue M, Lee SY, Hong ASO, Kauvar I, et al. Modulation of prefrontal cortex excitation/inhibition balance rescues social behavior in CNTNAP2-deficient mice. Sci Transl Med. 2017;9:eaah6733. pii

    Article  PubMed  PubMed Central  Google Scholar 

  53. Han S, Tai C, Westenbroek RE, Yu FH, Cheah CS, Potter GB, et al. Autistic-like behaviour in Scn1a+/− mice and rescue by enhanced GABA-mediated neurotransmission. Nature. 2012;489:385–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Han S, Tai C, Jones CJ, Scheuer T, Catterall WA. Enhancement of inhibitory neurotransmission by GABAA receptors havingalpha2,3-subunits ameliorates behavioral deficits in a mouse model of autism. Neuron. 2014;81:1282–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Gogolla N, Takesian AE, Feng G, Fagiolini M, Hensch TK. Sensory integration in mouse insular cortex reflects GABA circuit maturation. Neuron. 2014;83:894–905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Jung EM, Moffat JJ, Liu J, Dravid SM, Gurumurthy CB, Kim WY. Arid1b haploinsufficiency disrupts cortical interneuron development and mouse behavior. Nat Neurosci. 2017;20:1694–707.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Donegan JJ, Tyson JA, Branch SY, Beckstead MJ, Anderson SA, Lodge DJ. Stem cell-derived interneuron transplants as a treatment for schizophrenia: preclinical validation in a rodent model. Mol Psychiatry. 2017;22:1492–501.

    Article  CAS  PubMed  Google Scholar 

  58. Bateup HS, Johnson CA, Denefrio CL, Saulnier JL, Kornacker K, Sabatini BL. Excitatory/inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosis. Neuron. 2013;78:510–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kim YJ, Khoshkhoo S, Frankowski JC, Zhu B, Abbasi S, Lee S, et al. Chd2 is necessary for neural circuit development and long-term memory. Neuron. 2018;100:1180–93.

    Article  CAS  PubMed  Google Scholar 

  60. Mierau SB, Patrizi A, Hensch TK, Fagiolini M. Cell-specific regulation of N-Methyl-D-aspartate receptor maturation by Mecp2 in cortical circuits. Biol Psychiatry. 2016;79:746–54.

    Article  CAS  PubMed  Google Scholar 

  61. Chao HT, Chen H, Samaco RC, Xue M, Chahrour M, Yoo J, et al. Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes. Nature. 2010;468:263–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Vogt D, Cho KK, Lee AT, Sohal VS, Rubenstein JL. The parvalbumin/somatostatin ratio is increased in Pten mutant mice and by human PTEN ASD alleles. Cell Rep. 2015;11:944–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Cho KK, Hoch R, Lee AT, Patel T, Rubenstein JL, Sohal VS. Gamma rhythms link prefrontal interneuron dysfunction with cognitive inflexibility in Dlx5/6(+/−) mice. Neuron. 2015;85:1332–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Mathalon DH, Sohal VS. Neural oscillations and synchrony in brain dysfunction and neuropsychiatric disorders: it’s about time. JAMA Psychiatry. 2015;72:840–4.

    Article  PubMed  Google Scholar 

  65. Vogt D, Cho KKA, Shelton SM, Paul A, Huang ZJ, Sohal VS, et al. Mouse Cntnap2 and human CNTNAP2 ASD alleles cell autonomously regulate PV+cortical interneurons. Cereb Cortex. 2017;28:1–12.

    Article  Google Scholar 

  66. Brumback AC, Ellwood IT, Kjaerby C, Iafrati J, Robinson S, Lee AT, et al. Identifying specific prefrontal neurons that contribute to autism-associated abnormalities in physiology and social behavior. Mol Psychiatry. 2018;23:2078–89.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Khoshkhoo S, Vogt D, Sohal VS. Dynamic, cell-type-specific roles for GABAergic interneurons in a mouse model of optogenetically inducible seizures. Neuron. 2017;93:291–8.

    Article  CAS  PubMed  Google Scholar 

  68. Brown C, Gruber T, Boucher J, Rippon G, Brock J. Gamma abnormalities during perception of illusory figures in autism. Cortex. 2005;41:364–76.

    Article  PubMed  Google Scholar 

  69. Orekhova EV, Stroganova TA, Nygren G, Tsetlin MM, Posikera IN, Gillberg C, et al. Excess of high frequency electroencephalogram oscillations in boys with autism. Biol Psychiatry. 2007;62:1022–9.

    Article  PubMed  Google Scholar 

  70. Rojas DC, Maharajh K, Teale P, Rogers SJ. Reduced neural synchronization of gamma-band MEG oscillations in first-degree relatives of children with autism. BMC Psychiatry. 2008;8:66.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Sun L, Grützner C, Bölte S, Wibral M, Tozman T, Schlitt S, et al. Impaired gamma-band activity during perceptual organization in adults with autism spectrum disorders: evidence for dysfunctional network activity in frontal-posterior cortices. J Neurosci. 2012;32:9563–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Port RG, Gaetz W, Bloy L, Wang D-J, Blaskey L, Kuschner ES, 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. 2017;10:593–607.

    Article  PubMed  Google Scholar 

  73. Lajiness-O’Neill R, Brennan JR, Moran JE, Richard AE, Flores AM, Swick C, et al. Patterns of altered neural synchrony in the default mode network in autism spectrum disorder revealed with magnetoencephalography (MEG): Relationship to clinical symptomatology. Autism Res. 2018;11:434–49.

    Article  PubMed  Google Scholar 

  74. Sohal VS, Zhang F, Yizhar O, Deisseroth K. Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature. 2009;459:698–702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Veit J, Hakim R, Jadi MP, Sejnowski TJ, Adesnik H. Cortical gamma band synchronization through somatostatin interneurons. Nat Neurosci. 2017;20:951–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Port RG, Berman J, Liu S, Featherstone RE, Roberts TPL, Siegel SJ. Parvalbumin cell ablation of NMDA-R1 leads to altered phase, but not amplitude, of gamma-band cross frequency coupling. Brain Connect. 2018. https://doi.org/10.1089/brain.2018.0639.

    Article  Google Scholar 

  77. Robertson CE, Ratai EM, Kanwisher N. Reduced GABAerGic action in the autistic brain. Curr Biol. 2016;26:80–85.

    Article  CAS  PubMed  Google Scholar 

  78. Horder J, Petrinovic MM, Mendez MA, Bruns A, Takumi T, Spooren W, et al. Glutamate and GABA in autism spectrum disorder—a translational magnetic resonance spectroscopy study in man and rodent models. Transl Psychiatry. 2018;8:106.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Ajram LA, Horder J, Mendez MA, Galanopoulos A, Brennan LP, Wichers RH, et al. Shifting brain inhibitory balance and connectivity of the prefrontal cortex of adults with autism spectrum disorder. Transl Psychiatry. 2017;7:e1137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Mackenzie Howard for discussions. VSS is supported by NIMH (R01 MH100292 and R01 MH106507). JLRR is supported by Nina Ireland, the Simons Foundation (SFARI #309279), NINDS R01 NS34661, NIMH R01 MH081880, and NIMH R37 MH049428.

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  1. Department of Psychiatry, Weill Institute for Neurosciences, and Kavli Institute for Fundamental Neuroscience, University of California San Francisco, San Francisco, CA, 94143, USA

    Vikaas S. Sohal & John L. R. Rubenstein

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  1. Vikaas S. Sohal
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Correspondence to Vikaas S. Sohal or John L. R. Rubenstein.

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JLRR is cofounder, stockholder, and currently on the scientific board of Neurona, a company studying the potential therapeutic use of interneuron transplantation. VSS receives research funding from Neurona.

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Sohal, V.S., Rubenstein, J.L.R. Excitation-inhibition balance as a framework for investigating mechanisms in neuropsychiatric disorders. Mol Psychiatry 24, 1248–1257 (2019). https://doi.org/10.1038/s41380-019-0426-0

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