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.

  • Article
  • Published:

Developmental loss of ErbB4 in PV interneurons disrupts state-dependent cortical circuit dynamics

Molecular Psychiatry volume 28, pages 3133–3143 (2023)Cite this article

Subjects

Abstract

GABAergic inhibition plays an important role in the establishment and maintenance of cortical circuits during development. Neuregulin 1 (Nrg1) and its interneuron-specific receptor ErbB4 are key elements of a signaling pathway critical for the maturation and proper synaptic connectivity of interneurons. Using conditional deletions of the ERBB4 gene in mice, we tested the role of this signaling pathway at two developmental timepoints in parvalbumin-expressing (PV) interneurons, the largest subpopulation of cortical GABAergic cells. Loss of ErbB4 in PV interneurons during embryonic, but not late postnatal development leads to alterations in the activity of excitatory and inhibitory cortical neurons, along with severe disruption of cortical temporal organization. These impairments emerge by the end of the second postnatal week, prior to the complete maturation of the PV interneurons themselves. Early loss of ErbB4 in PV interneurons also results in profound dysregulation of excitatory pyramidal neuron dendritic architecture and a redistribution of spine density at the apical dendritic tuft. In association with these deficits, excitatory cortical neurons exhibit normal tuning for sensory inputs, but a loss of state-dependent modulation of the gain of sensory responses. Together these data support a key role for early developmental Nrg1/ErbB4 signaling in PV interneurons as a powerful mechanism underlying the maturation of both the inhibitory and excitatory components of cortical circuits.

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: Early, but not late, ErbB4 deletion from PV interneurons alters cortical firing and state transitions.
Fig. 2: Early loss of ErbB4 in PV cells disrupts the temporal organization of neocortical activity.
Fig. 3: Early PV ErbB4 deletion impairs excitatory pyramidal neuron morphology.
Fig. 4: ErbB4 mutants exhibit reduced visual response modulation but intact selectivity.

Similar content being viewed by others

Code availability

Analysis was performed using custom Matlab scripts, available from the authors on request.

References

  1. Allene C, Cattani A, Ackman JB, Bonifazi P, Aniksztejn L, Ben-Ari Y, et al. Sequential generation of two distinct synapse-driven network patterns in developing neocortex. J Neurosci. 2008;28:12851–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Cossart R. The maturation of cortical interneuron diversity: how multiple developmental journeys shape the emergence of proper network function. Curr Opin Neurobiol. 2011;21:160–8.

    Article  CAS  PubMed  Google Scholar 

  3. Modol L, Sousa VH, Malvache A, Tressard T, Baude A, Cossart R. Spatial embryonic origin delineates GABAergic hub neurons driving network dynamics in the developing entorhinal cortex. Cereb Cortex. 2017;27:4649–61.

    Article  PubMed  Google Scholar 

  4. Takesian AE, Hensch TK. Balancing plasticity/stability across brain development. Prog Brain Res. 2013;207:3–34.

    Article  PubMed  Google Scholar 

  5. Rossignol E. Genetics and function of neocortical GABAergic interneurons in neurodevelopmental disorders. Neural Plast. 2011;2011:649325.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Cardin JA. Inhibitory interneurons regulate temporal precision and correlations in cortical circuits. Trends Neurosci. 2018;41:689–700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hanganu-Opatz IL, Butt SJB, Hippenmeyer S, De Marco Garcia NV, Cardin JA, Voytek B, et al. The logic of developing neocortical circuits in health and disease. J Neurosci. 2021;41:813–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Abe Y, Namba H, Kato T, Iwakura Y, Nawa H. Neuregulin-1 signals from the periphery regulate AMPA receptor sensitivity and expression in GABAergic interneurons in developing neocortex. J Neurosci. 2011;31:5699–709.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Batista-Brito R, Vinck M, Ferguson KA, Chang JT, Laubender D, Lur G, et al. Developmental dysfunction of VIP interneurons impairs cortical circuits. Neuron. 2017;95:884–95.e889.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Del Pino I, Garcia-Frigola C, Dehorter N, Brotons-Mas JR, Alvarez-Salvado E, Martinez de Lagran M, et al. Erbb4 deletion from fast-spiking interneurons causes schizophrenia-like phenotypes. Neuron. 2013;79:1152–68.

    Article  PubMed  Google Scholar 

  11. Fazzari P, Paternain AV, Valiente M, Pla R, Lujan R, Lloyd K, et al. Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling. Nature. 2010;464:1376–80.

    Article  CAS  PubMed  Google Scholar 

  12. Neddens J, Buonanno A. Selective populations of hippocampal interneurons express ErbB4 and their number and distribution is altered in ErbB4 knockout mice. Hippocampus. 2010;20:724–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Vullhorst D, Neddens J, Karavanova I, Tricoire L, Petralia RS, McBain CJ, et al. Selective expression of ErbB4 in interneurons, but not pyramidal cells, of the rodent hippocampus. J Neurosci. 2009;29:12255–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yau HJ, Wang HF, Lai C, Liu FC. Neural development of the neuregulin receptor ErbB4 in the cerebral cortex and the hippocampus: preferential expression by interneurons tangentially migrating from the ganglionic eminences. Cereb Cortex. 2003;13:252–64.

    Article  PubMed  Google Scholar 

  15. Lai C, Lemke G. An extended family of protein-tyrosine kinase genes differentially expressed in the vertebrate nervous system. Neuron. 1991;6:691–704.

    Article  CAS  PubMed  Google Scholar 

  16. Huang YZ, Won S, Ali DW, Wang Q, Tanowitz M, Du QS, et al. Regulation of neuregulin signaling by PSD-95 interacting with ErbB4 at CNS synapses. Neuron. 2000;26:443–55.

    Article  CAS  PubMed  Google Scholar 

  17. Flames N, Long JE, Garratt AN, Fischer TM, Gassmann M, Birchmeier C, et al. Short- and long-range attraction of cortical GABAergic interneurons by neuregulin-1. Neuron. 2004;44:251–61.

    Article  CAS  PubMed  Google Scholar 

  18. Ting AK, Chen Y, Wen L, Yin DM, Shen C, Tao Y, et al. Neuregulin 1 promotes excitatory synapse development and function in GABAergic interneurons. J Neurosci. 2011;31:15–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Exposito-Alonso D, Osorio C, Bernard C, Pascual-Garcia S, Del Pino I, Marin O, et al. Subcellular sorting of neuregulins controls the assembly of excitatory-inhibitory cortical circuits. Elife. 2020;9:e57000.

  20. Wen L, Lu YS, Zhu XH, Li XM, Woo RS, Chen YJ, et al. Neuregulin 1 regulates pyramidal neuron activity via ErbB4 in parvalbumin-positive interneurons. Proc Natl Acad Sci USA. 2010;107:1211–6.

    Article  CAS  PubMed  Google Scholar 

  21. Sun Y, Ikrar T, Davis MF, Gong N, Zheng X, Luo ZD, et al. Neuregulin-1/ErbB4 signaling regulates visual cortical plasticity. Neuron. 2016;92:160–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Grieco SF, Holmes TC, Xu X. Neuregulin directed molecular mechanisms of visual cortical plasticity. J Comp Neurol. 2019;527:668–78.

    Article  PubMed  Google Scholar 

  23. Gu Y, Tran T, Murase S, Borrell A, Kirkwood A, Quinlan EM. Neuregulin-dependent regulation of fast-spiking interneuron excitability controls the timing of the critical period. J Neurosci. 2016;36:10285–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Del Pino I, Brotons-Mas JR, Marques-Smith A, Marighetto A, Frick A, Marin 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 

  25. Chen YJ, Zhang M, Yin DM, Wen L, Ting A, Wang P, et al. ErbB4 in parvalbumin-positive interneurons is critical for neuregulin 1 regulation of long-term potentiation. Proc Natl Acad Sci USA. 2010;107:21818–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yin DM, Chen YJ, Lu YS, Bean JC, Sathyamurthy A, Shen C, et al. Reversal of behavioral deficits and synaptic dysfunction in mice overexpressing neuregulin 1. Neuron. 2013;78:644–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Marques-Smith A, Lyngholm D, Kaufmann AK, Stacey JA, Hoerder-Suabedissen A, Becker EB, et al. A transient translaminar GABAergic interneuron circuit connects thalamocortical recipient layers in neonatal somatosensory cortex. Neuron. 2016;89:536–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Barros CS, Calabrese B, Chamero P, Roberts AJ, Korzus E, Lloyd K, et al. Impaired maturation of dendritic spines without disorganization of cortical cell layers in mice lacking NRG1/ErbB signaling in the central nervous system. Proc Natl Acad Sci USA. 2009;106:4507–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Tan Z, Robinson HL, Yin DM, Liu Y, Liu F, Wang H, et al. Dynamic ErbB4 activity in hippocampal-prefrontal synchrony and top-down attention in rodents. Neuron. 2018;98:380–93.e384.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Fogarty M, Grist M, Gelman D, Marin O, Pachnis V, Kessaris N. Spatial genetic patterning of the embryonic neuroepithelium generates GABAergic interneuron diversity in the adult cortex. J Neurosci. 2007;27:10935–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lavdas AA, Grigoriou M, Pachnis V, Parnavelas JG. The medial ganglionic eminence gives rise to a population of early neurons in the developing cerebral cortex. J Neurosci. 1999;19:7881–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Alifragis P, Liapi A, Parnavelas JG. Lhx6 regulates the migration of cortical interneurons from the ventral telencephalon but does not specify their GABA phenotype. J Neurosci. 2004;24:5643–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Cobos I, Calcagnotto ME, Vilaythong AJ, Thwin MT, Noebels JL, Baraban SC, et al. Mice lacking Dlx1 show subtype-specific loss of interneurons, reduced inhibition and epilepsy. Nat Neurosci. 2005;8:1059–68.

    Article  CAS  PubMed  Google Scholar 

  34. Cobos I, Long JE, Thwin MT, Rubenstein JL. Cellular patterns of transcription factor expression in developing cortical interneurons. Cereb Cortex. 2006;16:i82–88.

    Article  PubMed  Google Scholar 

  35. Liodis P, Denaxa M, Grigoriou M, Akufo-Addo C, Yanagawa Y, Pachnis V. Lhx6 activity is required for the normal migration and specification of cortical interneuron subtypes. J Neurosci. 2007;27:3078–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. del Rio JA, de Lecea L, Ferrer I, Soriano E. The development of parvalbumin-immunoreactivity in the neocortex of the mouse. Brain Res Dev Brain Res. 1994;81:247–59.

    Article  PubMed  Google Scholar 

  37. Chattopadhyaya B, Di Cristo G, Higashiyama H, Knott GW, Kuhlman SJ, Welker E, et al. Experience and activity-dependent maturation of perisomatic GABAergic innervation in primary visual cortex during a postnatal critical period. J Neurosci. 2004;24:9598–611.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hanson E, Armbruster M, Lau LA, Sommer ME, Klaft ZJ, Swanger SA, et al. Tonic activation of GluN2C/GluN2D-containing NMDA receptors by ambient glutamate facilitates cortical interneuron maturation. J Neurosci. 2019;39:3611–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Southwell DG, Paredes MF, Galvao RP, Jones DL, Froemke RC, Sebe JY, et al. Intrinsically determined cell death of developing cortical interneurons. Nature. 2012;491:109–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mossner JM, Batista-Brito R, Pant R, Cardin JA. Developmental loss of MeCP2 from VIP interneurons impairs cortical function and behavior. eLife. 2020;9:e55639.

  41. Vinck M, Batista-Brito R, Knoblich U, Cardin JA. Arousal and locomotion make distinct contributions to cortical activity patterns and visual encoding. Neuron. 2015;86:740–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Goldberg EM, Jeong HY, Kruglikov I, Tremblay R, Lazarenko RM, Rudy B. Rapid developmental maturation of neocortical FS cell intrinsic excitability. Cereb Cortex. 2011;21:666–82.

    Article  PubMed  Google Scholar 

  43. Gandal MJ, Edgar JC, Klook K, Siegel SJ. Gamma synchrony: towards a translational biomarker for the treatment-resistant symptoms of schizophrenia. Neuropharmacology. 2012;62:1504–18.

    Article  CAS  PubMed  Google Scholar 

  44. Uhlhaas PJ, Singer W. Abnormal neural oscillations and synchrony in schizophrenia. Nat Rev Neurosci. 2010;11:100–13.

    Article  CAS  PubMed  Google Scholar 

  45. Gibson JR, Beierlein M, Connors BW. Two networks of electrically coupled inhibitory neurons in neocortex. Nature. 1999;402:75–79.

    Article  CAS  PubMed  Google Scholar 

  46. Fries P. Neuronal gamma-band synchronization as a fundamental process in cortical computation. Annu Rev Neurosci. 2009;32:209–24.

    Article  CAS  PubMed  Google Scholar 

  47. Takesian AE, Bogart LJ, Lichtman JW, Hensch TK. Inhibitory circuit gating of auditory critical-period plasticity. Nat Neurosci. 2018;21:218–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Fishell G, Rudy B. Mechanisms of inhibition within the telencephalon: “where the wild things are”. Annu Rev Neurosci. 2011;34:535–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Tuncdemir SN, Wamsley B, Stam FJ, Osakada F, Goulding M, Callaway EM, et al. Early somatostatin interneuron connectivity mediates the maturation of deep layer cortical circuits. Neuron. 2016;89:521–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Lien AD, Scanziani M. Tuned thalamic excitation is amplified by visual cortical circuits. Nat Neurosci. 2013;16:1315–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ranganathan GN, Apostolides PF, Harnett MT, Xu NL, Druckmann S, Magee JC. Active dendritic integration and mixed neocortical network representations during an adaptive sensing behavior. Nat Neurosci. 2018;21:1583–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Jia H, Rochefort NL, Chen X, Konnerth A. Dendritic organization of sensory input to cortical neurons in vivo. Nature. 2010;464:1307–12.

    Article  CAS  PubMed  Google Scholar 

  53. Cruz-Martin A, El-Danaf RN, Osakada F, Sriram B, Dhande OS, Nguyen PL, et al. A dedicated circuit links direction-selective retinal ganglion cells to the primary visual cortex. Nature. 2014;507:358–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Roth MM, Dahmen JC, Muir DR, Imhof F, Martini FJ, Hofer SB. Thalamic nuclei convey diverse contextual information to layer 1 of visual cortex. Nat Neurosci. 2016;19:299–307.

    Article  CAS  PubMed  Google Scholar 

  55. Pakan JM, Lowe SC, Dylda E, Keemink SW, Currie SP, Coutts CA, et al. Behavioral-state modulation of inhibition is context-dependent and cell type specific in mouse visual cortex. Elife. 2016;5:5:e14985.

  56. Zhang S, Xu M, Kamigaki T, Hoang Do JP, Chang WC, Jenvay S, et al. Selective attention. Long-range and local circuits for top-down modulation of visual cortex processing. Science. 2014;345:660–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Fu Y, Tucciarone JM, Espinosa JS, Sheng N, Darcy DP, Nicoll RA, et al. A cortical circuit for gain control by behavioral state. Cell. 2014;156:1139–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Dipoppa M, Ranson A, Krumin M, Pachitariu M, Carandini M, Harris KD. Vision and locomotion shape the interactions between neuron types in mouse visual cortex. Neuron. 2018;98:602–15.e608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Rochefort NL, Narushima M, Grienberger C, Marandi N, Hill DN, Konnerth A. Development of direction selectivity in mouse cortical neurons. Neuron. 2011;71:425–32.

    Article  CAS  PubMed  Google Scholar 

  60. Niell CM, Stryker MP. Modulation of visual responses by behavioral state in mouse visual cortex. Neuron. 2010;65:472–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Cardin JA. Snapshots of the brain in action: local circuit operations through the lens of gamma oscillations. J Neurosci. 2016;36:10496–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Cardin JA, Carlen M, Meletis K, Knoblich U, Zhang F, Deisseroth K, et al. Driving fast-spiking cells induces gamma rhythm and controls sensory responses. Nature. 2009;459:663–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lewis DA, Lieberman JA. Catching up on schizophrenia: natural history and neurobiology. Neuron. 2000;28:325–34.

    Article  CAS  PubMed  Google Scholar 

  64. McGinley MJ, Vinck M, Reimer J, Batista-Brito R, Zagha E, Cadwell CR, et al. Waking state: rapid variations modulate neural and behavioral responses. Neuron. 2015;87:1143–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Tang L, Higley MJ. Layer 5 circuits in V1 differentially control visuomotor behavior. Neuron. 2020;105:346–54.e345.

    Article  CAS  PubMed  Google Scholar 

  66. Urban-Ciecko J, Jouhanneau JS, Myal SE, Poulet JFA, Barth AL. Precisely timed nicotinic activation drives SST inhibition in neocortical circuits. Neuron. 2018;97:611–25.e615.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Walker F, Mock M, Feyerabend M, Guy J, Wagener RJ, Schubert D, et al. Parvalbumin- and vasoactive intestinal polypeptide-expressing neocortical interneurons impose differential inhibition on Martinotti cells. Nat Commun. 2016;7:13664.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. 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 

  69. 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 

  70. David C, Schleicher A, Zuschratter W, Staiger JF. The innervation of parvalbumin-containing interneurons by VIP-immunopositive interneurons in the primary somatosensory cortex of the adult rat. Eur J Neurosci. 2007;25:2329–40.

    Article  PubMed  Google Scholar 

  71. Hamodi AS, Martinez Sabino A, Fitzgerald ND, Moschou D, Crair MC. Transverse sinus injections drive robust whole-brain expression of transgenes. Elife. 2020;9:e53639.

  72. Kim JY, Ash RT, Ceballos-Diaz C, Levites Y, Golde TE, Smirnakis SM, et al. Viral transduction of the neonatal brain delivers controllable genetic mosaicism for visualising and manipulating neuronal circuits in vivo. Eur J Neurosci. 2013;37:1203–20.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Cardin JA, Kumbhani RD, Contreras D, Palmer LA. Cellular mechanisms of temporal sensitivity in visual cortex neurons. J Neurosci. 2010;30:3652–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Pouille F, Scanziani M. Enforcement of temporal fidelity in pyramidal cells by somatic feed-forward inhibition. Science. 2001;293:1159–63.

    Article  CAS  PubMed  Google Scholar 

  75. Wehr M, Zador AM. Balanced inhibition underlies tuning and sharpens spike timing in auditory cortex. Nature. 2003;426:442–6.

    Article  CAS  PubMed  Google Scholar 

  76. Hasenstaub A, Shu Y, Haider B, Kraushaar U, Duque A, McCormick DA. Inhibitory postsynaptic potentials carry synchronized frequency information in active cortical networks. Neuron. 2005;47:423–35.

    Article  CAS  PubMed  Google Scholar 

  77. Vinck M, Womelsdorf T, Buffalo EA, Desimone R, Fries P. Attentional modulation of cell-class-specific gamma-band synchronization in awake monkey area v4. Neuron. 2013;80:1077–89.

    Article  CAS  PubMed  Google Scholar 

  78. Chiu CQ, Lur G, Morse TM, Carnevale NT, Ellis-Davies GC, Higley MJ. Compartmentalization of GABAergic inhibition by dendritic spines. Science. 2013;340:759–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Ko H, Hofer SB, Pichler B, Buchanan KA, Sjostrom PJ, Mrsic-Flogel TD. Functional specificity of local synaptic connections in neocortical networks. Nature. 2011;473:87–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Rockland KS, Pandya DN. Laminar origins and terminations of cortical connections of the occipital lobe in the rhesus monkey. Brain Res. 1979;179:3–20.

    Article  CAS  PubMed  Google Scholar 

  81. Felleman DJ, Van Essen DC. Distributed hierarchical processing in the primate cerebral cortex. Cereb Cortex. 1991;1:1–47.

    Article  CAS  PubMed  Google Scholar 

  82. Cauller LJ, Clancy B, Connors BW. Backward cortical projections to primary somatosensory cortex in rats extend long horizontal axons in layer I. J Comp Neurol. 1998;390:297–310.

    Article  CAS  PubMed  Google Scholar 

  83. Larkum ME, Senn W, Luscher HR. Top-down dendritic input increases the gain of layer 5 pyramidal neurons. Cereb Cortex. 2004;14:1059–70.

    Article  PubMed  Google Scholar 

  84. Larkum ME, Zhu JJ. Signaling of layer 1 and whisker-evoked Ca2+ and Na+ action potentials in distal and terminal dendrites of rat neocortical pyramidal neurons in vitro and in vivo. J Neurosci. 2002;22:6991–7005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Wang C, Waleszczyk WJ, Burke W, Dreher B. Feedback signals from cat’s area 21a enhance orientation selectivity of area 17 neurons. Exp Brain Res. 2007;182:479–90.

    Article  CAS  PubMed  Google Scholar 

  86. Keller AJ, Roth MM, Scanziani M. Feedback generates a second receptive field in neurons of the visual cortex. Nature. 2020;582:545–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Nassi JJ, Lomber SG, Born RT. Corticocortical feedback contributes to surround suppression in V1 of the alert primate. J Neurosci. 2013;33:8504–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Schiller J, Schiller Y, Stuart G, Sakmann B. Calcium action potentials restricted to distal apical dendrites of rat neocortical pyramidal neurons. J Physiol. 1997;505:605–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Bennett C, Arroyo S, Hestrin S. Subthreshold mechanisms underlying state-dependent modulation of visual responses. Neuron. 2013;80:350–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Hamm JP, Peterka DS, Gogos JA, Yuste R. Altered cortical ensembles in mouse models of schizophrenia. Neuron. 2017;94:153–67.e158.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Hamm JP, Yuste R. Somatostatin interneurons control a key component of mismatch negativity in mouse visual cortex. Cell Rep. 2016;16:597–604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Karouni M, Arulthas S, Larsson PG, Rytter E, Johannessen SI, Landmark CJ. Psychiatric comorbidity in patients with epilepsy: a population-based study. Eur J Clin Pharm. 2010;66:1151–60.

    Article  Google Scholar 

  93. Lee SH, Kim DW, Kim EY, Kim S, Im CH. Dysfunctional gamma-band activity during face structural processing in schizophrenia patients. Schizophr Res. 2010;119:191–7.

    Article  PubMed  Google Scholar 

  94. Martinez A, Hillyard SA, Dias EC, Hagler DJ Jr., Butler PD, Guilfoyle DN, et al. Magnocellular pathway impairment in schizophrenia: evidence from functional magnetic resonance imaging. J Neurosci. 2008;28:7492–7500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Serrano-Pedraza I, Romero-Ferreiro V, Read JC, Dieguez-Risco T, Bagney A, Caballero-Gonzalez M, et al. Reduced visual surround suppression in schizophrenia shown by measuring contrast detection thresholds. Front Psychol. 2014;5:1431.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Slaghuis WL. Spatio-temporal luminance contrast sensitivity and visual backward masking in schizophrenia. Exp Brain Res. 2004;156:196–211.

    Article  PubMed  Google Scholar 

  97. Tan HR, Lana L, Uhlhaas PJ. High-frequency neural oscillations and visual processing deficits in schizophrenia. Front Psychol. 2013;4:621.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Fishell G, Rudy B. Mechanisms of Inhibition within the telencephalon: “Where the Wild Things Are”. Annu Rev Neurosci. 2010.

  99. Rico B, Marin O. Neuregulin signaling, cortical circuitry development and schizophrenia. Curr Opin Genet Dev. 2011;21:262–70.

    Article  CAS  PubMed  Google Scholar 

  100. Mei L, Nave KA. Neuregulin-ERBB signaling in the nervous system and neuropsychiatric diseases. Neuron. 2014;83:27–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Lu CL, Wang YC, Chen JY, Lai IC, Liou YJ. Support for the involvement of the ERBB4 gene in schizophrenia: a genetic association analysis. Neurosci Lett. 2010;481:120–5.

    Article  CAS  PubMed  Google Scholar 

  102. Nicodemus KK, Luna A, Vakkalanka R, Goldberg T, Egan M, Straub RE, et al. Further evidence for association between ErbB4 and schizophrenia and influence on cognitive intermediate phenotypes in healthy controls. Mol Psychiatry. 2006;11:1062–5.

    Article  CAS  PubMed  Google Scholar 

  103. Silberberg G, Darvasi A, Pinkas-Kramarski R, Navon R. The involvement of ErbB4 with schizophrenia: association and expression studies. Am J Med Genet B Neuropsychiatr Genet. 2006;141B:142–8.

    Article  CAS  PubMed  Google Scholar 

  104. Law AJ, Kleinman JE, Weinberger DR, Weickert CS. Disease-associated intronic variants in the ErbB4 gene are related to altered ErbB4 splice-variant expression in the brain in schizophrenia. Hum Mol Genet. 2007;16:129–41.

    Article  CAS  PubMed  Google Scholar 

  105. Joshi D, Fullerton JM, Weickert CS. Elevated ErbB4 mRNA is related to interneuron deficit in prefrontal cortex in schizophrenia. J Psychiatr Res. 2014;53:125–32.

    Article  PubMed  Google Scholar 

  106. Chung DW, Volk DW, Arion D, Zhang Y, Sampson AR, Lewis DA. Dysregulated ErbB4 splicing in schizophrenia: selective effects on parvalbumin expression. Am J Psychiatry. 2016;173:60–8.

    Article  PubMed  Google Scholar 

  107. Agim ZS, Esendal M, Briollais L, Uyan O, Meschian M, Martinez LA, et al. Discovery, validation and characterization of Erbb4 and Nrg1 haplotypes using data from three genome-wide association studies of schizophrenia. PLoS One. 2013;8:e53042.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Shi J, Levinson DF, Duan J, Sanders AR, Zheng Y, Pe’er I, et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature. 2009;460:753–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Pardiñas AF, Holmans P, Pocklington AJ, Escott-Price V, Ripke S, Carrera N, et al. Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Nat Genet. 2018;50:381–9.

  110. Mojarad BA, Engchuan W, Trost B, Backstrom I, Yin Y, Thiruvahindrapuram B, et al. Genome-wide tandem repeat expansions contribute to schizophrenia risk. Mol Psychiatry. 2022;27:3692–8.

  111. Karl T, Duffy L, Scimone A, Harvey RP, Schofield PR. Altered motor activity, exploration and anxiety in heterozygous neuregulin 1 mutant mice: implications for understanding schizophrenia. Genes Brain Behav. 2007;6:677–87.

    Article  CAS  PubMed  Google Scholar 

  112. Shamir A, Kwon OB, Karavanova I, Vullhorst D, Leiva-Salcedo E, Janssen MJ, et al. The importance of the NRG-1/ErbB4 pathway for synaptic plasticity and behaviors associated with psychiatric disorders. J Neurosci. 2012;32:2988–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Wang H, Liu F, Chen W, Sun X, Cui W, Dong Z, et al. Genetic recovery of ErbB4 in adulthood partially restores brain functions in null mice. Proc Natl Acad Sci USA. 2018;115:13105–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Fiori LM, Kos A, Lin R, Theroux JF, Lopez JP, Kuhne C, et al. miR-323a regulates ERBB4 and is involved in depression. Mol Psychiatry. 2021;26:4191–204.

    Article  CAS  PubMed  Google Scholar 

  115. Wang H, Cui W, Chen W, Liu F, Dong Z, Xing G, et al. The laterodorsal tegmentum-ventral tegmental area circuit controls depression-like behaviors by activating ErbB4 in DA neurons. Mol Psychiatry. 2023;28:1027–45.

  116. Bi LL, Sun XD, Zhang J, Lu YS, Chen YH, Wang J, et al. Amygdala NRG1-ErbB4 is critical for the modulation of anxiety-like behaviors. Neuropsychopharmacology. 2015;40:974–86.

    Article  CAS  PubMed  Google Scholar 

  117. Chen M, Li Y, Liu Y, Xu H, Bi LL. Neuregulin-1-dependent control of amygdala microcircuits is critical for fear extinction. Neuropharmacology. 2021;201:108842.

    Article  CAS  PubMed  Google Scholar 

  118. Li B, Woo RS, Mei L, Malinow R. The neuregulin-1 receptor erbB4 controls glutamatergic synapse maturation and plasticity. Neuron. 2007;54:583–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Vinck M, Battaglia FP, Womelsdorf T, Pennartz C. Improved measures of phase-coupling between spikes and the Local Field Potential. J Comput Neurosci. 2012;33:53–75.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Dr. M.J. Higley for helpful comments on the manuscript, Dr. A. Koleske for the ErbB4F/F mice, and Dr. B. Li for the ErbB4 plasmid. This work was supported by a Brown-Coxe fellowship, a Jane Coffin Childs Fellowship, a NARSAD Young Investigator Award, a Simons Bridge to Independence Award, and a Whitehall Award to RBB; a Ruth L. Kirschstein Predoctoral Fellowship F31HD101360 to CW; a Rubicon fellowship and a Human Frontiers Postdoctoral Fellowship to MV; and NIH R01 MH102365, NIH R01 EY022951, a Smith Family Award for Excellence in Biomedical Research, a Klingenstein Fellowship Award, an Alfred P. Sloan Fellowship, a NARSAD Young Investigator Award, and a McKnight Fellowship to JAC. This work was further supported by the Yale Core Grant for Vision Research NIH P30 EY02678.

Author information

Author notes

  1. Antara Majumdar

    Present address: Department of Physiology, Anatomy and Genetics, University of Oxford, Sherrington Building, Sherrington Road, Oxford, OX1 3PT, England

  2. Kasra Nikouei

    Present address: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

  3. Martin Vinck

    Present address: Ernst Strüngmann Institute (ESI) for Neuroscience in Cooperation with Max Planck Society, Deutschordenstraße 46, 60528, Frankfurt, Germany

Authors and Affiliations

  1. Department of Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Ave, The Bronx, NY, 10461, USA

    Renata Batista-Brito & Claire Ward

  2. Department of Neuroscience, Yale University School of Medicine, 333 Cedar St., New Haven, CT, 06520, USA

    Renata Batista-Brito, Antara Majumdar, Alejandro Nuño, Clayton Barnes, Kasra Nikouei, Martin Vinck & Jessica A. Cardin

  3. Department of Psychiatry and Behavioral Sciences, Einstein College of Medicine, 1300 Morris Park Ave, The Bronx, NY, 10461, USA

    Renata Batista-Brito

  4. Department of Genetics, Einstein College of Medicine, 1300 Morris Park Ave, The Bronx, NY, 10461, USA

    Renata Batista-Brito

  5. Kavli Institute of Neuroscience, Yale University, 333 Cedar St., New Haven, CT, 06520, USA

    Jessica A. Cardin

  6. Wu Tsai Institute, Yale University, 100 College St., New Haven, CT, 06520, USA

    Jessica A. Cardin

Authors
  1. Renata Batista-Brito
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Antara Majumdar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alejandro Nuño
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Claire Ward
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Clayton Barnes
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kasra Nikouei
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Martin Vinck
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jessica A. Cardin
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

RBB, MV, AM, AN, and JAC designed experiments. RBB, CB, and JAC performed in vivo electrophysiology recordings. RBB, MV, CB, and JAC analyzed in vivo electrophysiology data. AM and AN performed virus injections and cellular reconstructions and analyzed anatomical data. RBB, CW, and KN performed immunohistochemistry. RBB, AM, AN, and JAC wrote the manuscript.

Corresponding authors

Correspondence to Renata Batista-Brito or Jessica A. Cardin.

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.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Batista-Brito, R., Majumdar, A., Nuño, A. et al. Developmental loss of ErbB4 in PV interneurons disrupts state-dependent cortical circuit dynamics. Mol Psychiatry 28, 3133–3143 (2023). https://doi.org/10.1038/s41380-023-02066-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-023-02066-3

This article is cited by

Search

Advanced search

Quick links