Advertisement

Experimental Brain Research

, Volume 237, Issue 12, pp 3351–3362 | Cite as

NRG1–ErbB4 signaling promotes functional recovery in a murine model of traumatic brain injury via regulation of GABA release

  • Weike Deng
  • Fei LuoEmail author
  • Bao-ming Li
  • Lin Mei
Research Article

Abstract

Traumatic brain injury (TBI) is a serious health problem in the world. However, little is known about the pathogenesis and molecular mechanisms of TBI. Here, we show that TBI activates neuregulin 1 (NRG1)-ErbB4 signaling, with an increased expression of NRG1 and ErbB4 in the traumatic region. Specifically knocking out ErbB4 in parvalbumin-positive (PV+) interneurons exacerbates motor function deficits in mice after TBI. Consistently, PV-ErbB4−/− mice showed larger necrotic area and more edema when compared with PV-ErbB4+/+ mice. Replenishment of NRG1 through intranasal application of the recombinant protein in PV-ErbB4+/+ mice enhanced neurological function. Moreover, using an in vitro neuronal culture system, we found that NRG1–ErbB4 signaling protects neurons from glutamate-induced death, and such protective effects could be diminished by GABA receptor antagonist. These results indicate that NRG-ErbB4 signaling protects cortical neurons from TBI-induced damage, and such effect is probably mediated by promoting GABA activity. Taken together, these findings unveil a previously unappreciated role for NRG1-ErB4 signaling in preventing neuronal cell death during functional recovery after TBI.

Keywords

NRG1–ErbB4 signaling Traumatic brain injury Neuroprotection GABA 

Notes

Funding

This research was supported by the National Natural Science Foundation of China (31971035, 81471116, 31771182, 81560196), and the Natural Science Foundation of Jiangxi Province (20171ACB20002).

Compliance with ethical standards

Conflict of interest

The authors declare no financial conflict of interest regarding the publication of this article.

Supplementary material

221_2019_5680_MOESM1_ESM.docx (646 kb)
Supplementary material 1 (DOCX 645 kb)

References

  1. Adelson JD, Barreto GE, Xu L et al (2012) Neuroprotection from stroke in the absence of MHCI or PirB. Neuron 73:1100–1107.  https://doi.org/10.1016/j.neuron.2012.01.020 CrossRefPubMedPubMedCentralGoogle Scholar
  2. Alexander MP (1995) Mild traumatic brain injury: pathophysiology, natural history, and clinical management. Neurology 45:1253–1260CrossRefGoogle Scholar
  3. Bean JC, Lin TW, Sathyamurthy A, Liu F, Yin DM, Xiong WC, Mei L (2014) Genetic labeling reveals novel cellular targets of schizophrenia susceptibility gene: distribution of GABA and non-GABA ErbB4-positive cells in adult mouse brain. J Neurosci 34:13549–13566.  https://doi.org/10.1523/JNEUROSCI.2021-14.2014 CrossRefPubMedPubMedCentralGoogle Scholar
  4. Bigler ED (2003) Neurobiology and neuropathology underlie the neuropsychological deficits associated with traumatic brain injury. Arch Clin Neuropsychol 18:595–621CrossRefGoogle Scholar
  5. Blennow K, Hardy J, Zetterberg H (2012) The neuropathology and neurobiology of traumatic brain injury. Neuron 76:886–899.  https://doi.org/10.1016/j.neuron.2012.11.021 CrossRefPubMedGoogle Scholar
  6. Bramlett HM, Dietrich WD (2015) Long-Term Consequences of Traumatic Brain Injury: current Status of Potential Mechanisms of Injury and Neurological Outcomes. J Neurotrauma 32:1834–1848.  https://doi.org/10.1089/neu.2014.3352 CrossRefPubMedPubMedCentralGoogle Scholar
  7. Brickler TR, Hazy A, Guilhaume Correa F et al (2018) Angiopoietin/Tie2 axis regulates the age-at-injury cerebrovascular response to traumatic brain injury. J Neurosci 38:9618–9634.  https://doi.org/10.1523/JNEUROSCI.0914-18.2018 CrossRefPubMedPubMedCentralGoogle Scholar
  8. Bublil EM, Yarden Y (2007) The EGF receptor family: spearheading a merger of signaling and therapeutics. Curr Opin Cell Biol 19:124–134.  https://doi.org/10.1016/j.ceb.2007.02.008 CrossRefPubMedGoogle Scholar
  9. Buonanno A (2010) The neuregulin signaling pathway and schizophrenia: from genes to synapses and neural circuits. Brain Res Bull 83:122–131.  https://doi.org/10.1016/j.brainresbull.2010.07.012 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Chen YJ, Zhang M, Yin DM et al (2010) ErbB4 in parvalbumin-positive interneurons is critical for neuregulin 1 regulation of long-term potentiation. Proc Natl Acad Sci USA 107:21818–21823.  https://doi.org/10.1073/pnas.1010669107 CrossRefPubMedGoogle Scholar
  11. Costa C, Leone G, Saulle E, Pisani F, Bernardi G, Calabresi P (2004) Coactivation of GABA(A) and GABA(B) receptor results in neuroprotection during in vitro ischemia. Stroke 35:596–600.  https://doi.org/10.1161/01.STR.0000113691.32026.06 CrossRefPubMedGoogle Scholar
  12. DeFazio RA, Raval AP, Lin HW, Dave KR, Della-Morte D, Perez-Pinzon MA (2009) GABA synapses mediate neuroprotection after ischemic and epsilonPKC preconditioning in rat hippocampal slice cultures. J Cereb Blood Flow Metab 29:375–384.  https://doi.org/10.1038/jcbfm.2008.126 CrossRefPubMedGoogle Scholar
  13. Dorsett CR, McGuire JL, DePasquale EA, Gardner AE, Floyd CL, McCullumsmith RE (2017) Glutamate neurotransmission in rodent models of traumatic brain injury. J Neurotrauma 34:263–272.  https://doi.org/10.1089/neu.2015.4373 CrossRefPubMedPubMedCentralGoogle Scholar
  14. Erlich S, Shohami E, Pinkas-Kramarski R (2000) Closed head injury induces up-regulation of ErbB-4 receptor at the site of injury. Mol Cell Neurosci 16:597–608.  https://doi.org/10.1006/mcne.2000.0894 CrossRefPubMedGoogle Scholar
  15. Faden AI, Demediuk P, Panter SS, Vink R (1989) The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 244:798–800CrossRefGoogle Scholar
  16. Falls DL (2003) Neuregulins: functions, forms, and signaling strategies. Exp Cell Res 284:14–30CrossRefGoogle Scholar
  17. Fazzari P, Paternain AV, Valiente M et al (2010) Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling. Nature 464:1376–1380.  https://doi.org/10.1038/nature08928 CrossRefPubMedGoogle Scholar
  18. Garcia-Rivello H, Taranda J, Said M et al (2005) Dilated cardiomyopathy in Erb-b4-deficient ventricular muscle. Am J Physiol Heart Circ Physiol 289:H1153–H1160.  https://doi.org/10.1152/ajpheart.00048.2005 CrossRefPubMedGoogle Scholar
  19. Guan YF, Wu CY, Fang YY et al (2015) Neuregulin 1 protects against ischemic brain injury via ErbB4 receptors by increasing GABAergic transmission. Neuroscience 307:151–159.  https://doi.org/10.1016/j.neuroscience.2015.08.047 CrossRefPubMedGoogle Scholar
  20. Harrison PJ, Law AJ (2006) Neuregulin 1 and schizophrenia: genetics, gene expression, and neurobiology. Biol Psychiat 60:132–140.  https://doi.org/10.1016/j.biopsych.2005.11.002 CrossRefPubMedGoogle Scholar
  21. Holmes WE, Sliwkowski MX, Akita RW et al (1992) Identification of heregulin, a specific activator of p185erbB2. Science 256:1205–1210CrossRefGoogle Scholar
  22. Horita Y, Honmou O, Harada K, Houkin K, Hamada H, Kocsis JD (2006) Intravenous administration of glial cell line-derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in the adult rat. J Neurosci Res 84:1495–1504.  https://doi.org/10.1002/jnr.21056 CrossRefPubMedPubMedCentralGoogle Scholar
  23. Jassam YN, Izzy S, Whalen M, McGavern DB, El Khoury J (2017) Neuroimmunology of traumatic brain injury: time for a paradigm shift. Neuron 95:1246–1265.  https://doi.org/10.1016/j.neuron.2017.07.010 CrossRefPubMedPubMedCentralGoogle Scholar
  24. Johnson VE, Stewart W, Smith DH (2013) Axonal pathology in traumatic brain injury. Exp Neurol 246:35–43.  https://doi.org/10.1016/j.expneurol.2012.01.013 CrossRefPubMedGoogle Scholar
  25. Kierans AS, Kirov II, Gonen O et al (2014) Myoinositol and glutamate complex neurometabolite abnormality after mild traumatic brain injury. Neurology 82:521–528.  https://doi.org/10.1212/WNL.0000000000000105 CrossRefPubMedPubMedCentralGoogle Scholar
  26. Kim JJ, Kang YJ, Shin SA et al (2016) Phlorofucofuroeckol improves glutamate-induced neurotoxicity through modulation of oxidative stress-mediated mitochondrial dysfunction in PC12 Cells. PLoS ONE 11:e0163433.  https://doi.org/10.1371/journal.pone.0163433 CrossRefPubMedPubMedCentralGoogle Scholar
  27. Kozlovskaya L, Abou-Kaoud M, Stepensky D (2014) Quantitative analysis of drug delivery to the brain via nasal route. J Control Release 189:133–140.  https://doi.org/10.1016/j.jconrel.2014.06.053 CrossRefPubMedGoogle Scholar
  28. Li Y, Xu Z, Ford GD, Croslan DR, Cairobe T, Li Z, Ford BD (2007) Neuroprotection by neuregulin-1 in a rat model of permanent focal cerebral ischemia. Brain Res 1184:277–283.  https://doi.org/10.1016/j.brainres.2007.09.037 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Li Y, Lein PJ, Liu C et al (2012) Neuregulin-1 is neuroprotective in a rat model of organophosphate-induced delayed neuronal injury. Toxicol Appl Pharmacol 262:194–204.  https://doi.org/10.1016/j.taap.2012.05.001 CrossRefPubMedPubMedCentralGoogle Scholar
  30. Lu YM, Gao YP, Tao RR et al (2016) Calpain-dependent ErbB4 cleavage is involved in brain ischemia-induced neuronal death. Mol Neurobiol 53:2600–2609.  https://doi.org/10.1007/s12035-015-9275-2 CrossRefPubMedGoogle Scholar
  31. Maas AI, Stocchetti N, Bullock R (2008) Moderate and severe traumatic brain injury in adults. Lancet Neurol 7:728–741.  https://doi.org/10.1016/s1474-4422(08)70164-9 CrossRefPubMedGoogle Scholar
  32. Madisen L, Zwingman TA, Sunkin SM et al (2010) A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci 13:133–140.  https://doi.org/10.1038/nn.2467 CrossRefPubMedGoogle Scholar
  33. Mayor D, Tymianski M (2018) Neurotransmitters in the mediation of cerebral ischemic injury. Neuropharmacology 134:178–188.  https://doi.org/10.1016/j.neuropharm.2017.11.050 CrossRefPubMedGoogle Scholar
  34. Mei L, Nave KA (2014) Neuregulin-ERBB signaling in the nervous system and neuropsychiatric diseases. Neuron 83:27–49.  https://doi.org/10.1016/j.neuron.2014.06.007 CrossRefPubMedPubMedCentralGoogle Scholar
  35. Mei L, Xiong WC (2008) Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat Rev Neurosci 9:437–452.  https://doi.org/10.1038/nrn2392 CrossRefPubMedPubMedCentralGoogle Scholar
  36. Merkler D, Metz GA, Raineteau O, Dietz V, Schwab ME, Fouad K (2001) Locomotor recovery in spinal cord-injured rats treated with an antibody neutralizing the myelin-associated neurite growth inhibitor Nogo-A. J Neurosci 21:3665–3673CrossRefGoogle Scholar
  37. Miller DM, Singh IN, Wang JA, Hall ED (2015) Nrf2-ARE activator carnosic acid decreases mitochondrial dysfunction, oxidative damage and neuronal cytoskeletal degradation following traumatic brain injury in mice. Exp Neurol 264:103–110.  https://doi.org/10.1016/j.expneurol.2014.11.008 CrossRefPubMedGoogle Scholar
  38. Simon DW, McGeachy MJ, Bayir H, Clark RS, Loane DJ, Kochanek PM (2017) The far-reaching scope of neuroinflammation after traumatic brain injury. Nat Rev Neurol 13:171–191.  https://doi.org/10.1038/nrneurol.2017.13 CrossRefPubMedPubMedCentralGoogle Scholar
  39. Smith DH, Johnson VE, Stewart W (2013) Chronic neuropathologies of single and repetitive TBI: substrates of dementia? Nat Rev Neurol 9:211–221.  https://doi.org/10.1038/nrneurol.2013.29 CrossRefPubMedPubMedCentralGoogle Scholar
  40. Steinthorsdottir V, Stefansson H, Ghosh S et al (2004) Multiple novel transcription initiation sites for NRG1. Gene 342:97–105.  https://doi.org/10.1016/j.gene.2004.07.029 CrossRefPubMedGoogle Scholar
  41. Takada Y, Yonezawa A, Kume T, Katsuki H, Kaneko S, Sugimoto H, Akaike A (2003) Nicotinic acetylcholine receptor-mediated neuroprotection by donepezil against glutamate neurotoxicity in rat cortical neurons. J Pharmacol Exp Ther 306:772–777.  https://doi.org/10.1124/jpet.103.050104 CrossRefPubMedGoogle Scholar
  42. Taylor CA, Bell JM, Breiding MJ, Xu L (2017) Traumatic brain injury-related emergency department visits, hospitalizations, and deaths—United States, 2007 and 2013. MMWR Surveill Summ 66:1–16.  https://doi.org/10.15585/mmwr.ss6609a1 CrossRefPubMedPubMedCentralGoogle Scholar
  43. Tidcombe H, Jackson-Fisher A, Mathers K, Stern DF, Gassmann M, Golding JP (2003) Neural and mammary gland defects in ErbB4 knockout mice genetically rescued from embryonic lethality. Proc Natl Acad Sci USA 100:8281–8286.  https://doi.org/10.1073/pnas.1436402100 CrossRefPubMedGoogle Scholar
  44. Washington PM, Forcelli PA, Wilkins T, Zapple DN, Parsadanian M, Burns MP (2012) The effect of injury severity on behavior: a phenotypic study of cognitive and emotional deficits after mild, moderate, and severe controlled cortical impact injury in mice. J Neurotrauma 29:2283–2296.  https://doi.org/10.1089/neu.2012.2456 CrossRefPubMedPubMedCentralGoogle Scholar
  45. Wen L, Lu YS, Zhu XH et al (2010) Neuregulin 1 regulates pyramidal neuron activity via ErbB4 in parvalbumin-positive interneurons. Proc Natl Acad Sci USA 107:1211–1216.  https://doi.org/10.1073/pnas.0910302107 CrossRefPubMedGoogle Scholar
  46. Woo RS, Li XM, Tao Y et al (2007) Neuregulin-1 enhances depolarization-induced GABA release. Neuron 54:599–610.  https://doi.org/10.1016/j.neuron.2007.04.009 CrossRefPubMedGoogle Scholar
  47. Xia Y, Pu H, Leak RK et al (2018) Tissue plasminogen activator promotes white matter integrity and functional recovery in a murine model of traumatic brain injury. Proc Natl Acad Sci USA 115:E9230–E9238.  https://doi.org/10.1073/pnas.1810693115 CrossRefPubMedGoogle Scholar
  48. Xu Z, Ford BD (2005) Upregulation of erbB receptors in rat brain after middle cerebral arterial occlusion. Neurosci Lett 375:181–186.  https://doi.org/10.1016/j.neulet.2004.11.039 CrossRefPubMedGoogle Scholar
  49. Xu Z, Jiang J, Ford G, Ford BD (2004) Neuregulin-1 is neuroprotective and attenuates inflammatory responses induced by ischemic stroke. Biochem Biophys Res Commun 322:440–446.  https://doi.org/10.1016/j.bbrc.2004.07.149 CrossRefPubMedGoogle Scholar
  50. Yang Y, Zhong Z, Wang B et al (2019) Early-life high-fat diet-induced obesity programs hippocampal development and cognitive functions via regulation of gut commensal Akkermansia muciniphila. Neuropsychopharmacology.  https://doi.org/10.1038/s41386-019-0437-1 CrossRefPubMedGoogle Scholar
  51. Zhao Z, Loane DJ, Murray MG 2nd, Stoica BA, Faden AI (2012) Comparing the predictive value of multiple cognitive, affective, and motor tasks after rodent traumatic brain injury. J Neurotrauma 29:2475–2489.  https://doi.org/10.1089/neu.2012.2511 CrossRefPubMedPubMedCentralGoogle Scholar
  52. Zhou C, Li C, Yu HM, Zhang F, Han D, Zhang GY (2008) Neuroprotection of gamma-aminobutyric acid receptor agonists via enhancing neuronal nitric oxide synthase (Ser847) phosphorylation through increased neuronal nitric oxide synthase and PSD95 interaction and inhibited protein phosphatase activity in cerebral ischemia. J Neurosci Res 86:2973–2983.  https://doi.org/10.1002/jnr.21728 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.School of Life ScienceNanchang UniversityNanchangPeople’s Republic of China
  2. 2.Institute of Life ScienceNanchang UniversityNanchangPeople’s Republic of China
  3. 3.Department of Neuroscience and Regenerative Medicine, Medical College of GeorgiaAugusta UniversityAugustaUSA
  4. 4.Charlie Norwood VA Medical CenterAugustaUSA

Personalised recommendations