Skip to main content
SpringerLink
Log in

Increased Seizure Susceptibility for Rats Subject to Early Life Hypoxia Might Be Associated with Brain Dysfunction of NRG1-ErbB4 Signaling in Parvalbumin Interneurons

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Neuregulin 1 (NRG1)–induced activation of ErbB4 in parvalbumin (PV) inhibitory interneurons is reported to serve as a critical endogenous negative-feedback mechanism to repress brain epileptogenesis. Here, we investigated the seizure susceptibility and the role of NRG1-ErbB4 signaling in PV interneurons in the suppression of epileptic seizures for rats subject to early life hypoxia. Neonatal postnatal day 5 (P5) rats were exposed to intermittent hypoxia (IH) or control (CON) room air for 10 days. In the prefrontal cortex (PFC) of P54 rats, we determined the impact of neonatal IH exposures on the expression of PV, NRG1, ErbB4, and phosphorylated ErbB4 (p-ErbB4) during the seizure induction. Seizure susceptibility tests with the common convulsant agent pentylenetetrazole (PEN) at P54 revealed that rats subject to neonatal hypoxia exposure developed faster and more serious epileptic seizures. Neonatal IH exposures (1) decreased the number of PV cells in the PFC of P54 rats; (2) interrupted the expression of NRG1 gene; and (3) altered the activity of NRG1 on PV interneurons in the PFC after the seizure induction. Intracerebroventricular delivery of exogenous NRG1 before seizure induction by PEN significantly reduced the seizure susceptibility for neonatal IH-exposed rats. The ErbB4 inhibitor AG1478 inhibited the exogenous NRG1’s effects on seizure susceptibility. Environmental enrichment (EE) rescued the abovementioned pathophysiological alterations and significantly attenuated the epileptic seizures after the seizure induction for neonatal IH-exposed rats. Our study indicated early life hypoxia exposure might increase the seizure susceptibility for rats and contribute to pathophysiological dysfunction of NRG1-ErbB4 signaling in PV interneurons in the suppression of epileptic seizures. EE might attenuate the increased seizure susceptibility for neonatal IH-exposed rats through rescuing pathophysiological alterations of NRG1-ErbB4 signaling in PV interneurons.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Atik A, Harding R, De Matteo R, Kondos-Devcic D, Cheong J, Doyle LW, Tolcos M (2017) Caffeine for apnea of prematurity: Effects on the developing brain. Neurotoxicology 58:94–102

    Article  CAS  Google Scholar 

  2. Laouafa S, Iturri P, Arias-Reyes C, Marcouiller F, Gonzales M, Joseph V, Bairam A, Soliz J (2019) Erythropoietin and caffeine exert similar protective impact against neonatal intermittent hypoxia: apnea of prematurity and sex dimorphism. Exp Neurol 320:112985

    Article  CAS  Google Scholar 

  3. Morton SU, Smith VC (2016) Treatment options for apnoea of prematurity. Arch Dis Child-Fetal 101:F352–F356

    Article  Google Scholar 

  4. Bartos M, Vida I, Jonas P (2007) Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks. Nat Rev Neurosci 8:45–56

    Article  CAS  Google Scholar 

  5. Komitova M, Xenos D, Salmaso N, Tran KM, Brand T, Schwartz ML, Ment L, Vaccarino FM (2013) Hypoxia-induced developmental delays of inhibitory interneurons are reversed by environmental enrichment in the postnatal mouse forebrain. J Neurosci 33:13375–13387

    Article  CAS  Google Scholar 

  6. Lewis DA, Curley AA, Glausier JR, Volk DW (2012) Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia Trends. Neurosci 35:57–67

    CAS  Google Scholar 

  7. Liang D, Li G, Liao X, Yu D, Wu J, Zhang M (2016) Developmental loss of parvalbumin-positive cells in the prefrontal cortex and psychiatric anxiety after intermittent hypoxia exposures in neonatal rats might be mediated by NADPH oxidase-2. Behav Brain Res 296:134–140

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  9. Whittington MA, Cunningham MO, LeBeau FE, Racca C, Traub RD (2011) Multiple origins of the cortical gamma rhythm. Dev Neurobiol 71:92–106

    Article  Google Scholar 

  10. Schwaller B, Tetko IV, Tandon P, Silveira DC, Vreugdenhil M, Henzi T, Potier M-C, Celio MR et al (2004) Parvalbumin deficiency affects network properties resulting in increased susceptibility to epileptic seizures. Mol Cell Neurosci 25:650–663

    Article  CAS  Google Scholar 

  11. Galeano P, Romero JI, Luque-Rojas MJ, Suarez J, Holubiec MI, Bisagno V, Santín LJ, De Fonseca FR et al (2013) Moderate and severe perinatal asphyxia induces differential effects on cocaine sensitization in adult rats. Synapse 67:553–567

    Article  CAS  Google Scholar 

  12. Goussakov I, Synowiec S, Yarnykh V, Drobyshevsky A (2019) Immediate and delayed decrease of long term potentiation and memory deficits after neonatal intermittent hypoxia. Int J Dev Neurosci 74:27–37

    Article  Google Scholar 

  13. Wang H, Liu F, Chen W, Sun X, Cui W, Dong Z, Zhao K, Zhang H et al (2018) Genetic recovery of ErbB4 in adulthood partially restores brain functions in null mice. Proc Natl Acad Sci U S A 115:13105–13110

    Article  CAS  Google Scholar 

  14. Tan GH, Liu YY, Hu XL, Yin DM, Mei L, Xiong ZQ (2011) Neuregulin 1 represses limbic epileptogenesis through ErbB4 in parvalbumin-expressing interneurons. Nat Neurosci 15:258–266

    Article  Google Scholar 

  15. Huang YZ, Won S, Ali DW, Wang Q, Tanowitz M, Du QS, Pelkey KA, Yang DJ et al (2000) Regulation of neuregulin signaling by PSD-95 interacting with ErbB4 at CNS synapses. Neuron 26:443–455

    Article  CAS  Google Scholar 

  16. Yau HJ, Wang HF, Lai C, Liu FC (2003) 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 13:252–264

    Article  Google Scholar 

  17. Woo RS, Li XM, Tao Y, Carpenter-Hyland E, Huang YZ, Weber J, Neiswender H, Dong XP (2007) Neuregulin-1 enhances depolarization-induced GABA release. Neuron 54:599–610

    Article  CAS  Google Scholar 

  18. Wen L, Lu YS, Zhu XH, Li XM, Woo RS, Chen YJ, Yin DM, Lai C et al (2010) Neuregulin 1 regulates pyramidal neuron activity via ErbB4 in parvalbumin-positive interneurons. Proc Natl Acad Sci USA 107:1211–1216

    Article  CAS  Google Scholar 

  19. Eilam R, Pinkas-Kramarski R, Ratzkin BJ, Segal M, Yarden Y (1998) Activity-dependent regulation of Neu differentiation factor neuregulin expression in rat brain. Proc Natl Acad Sci USA 95:1888–1893

    Article  CAS  Google Scholar 

  20. Ozaki M, Itoh K, Miyakawa Y, Kishida H, Hashikawa T (2004) Protein processing and releases of neuregulin-1 are regulated in an activity-dependent manner. J Neurochem 91:176–188

    Article  CAS  Google Scholar 

  21. McNamara JO, Huang YZ, Leonard AS (2006) Molecular signaling mechanisms underlying epileptogenesis. Sci Stke 356:re12

    Google Scholar 

  22. Morimoto K, Fahnestock M, Racine RJ (2004) Kindling and status epilepticus models of epilepsy: rewiring the brain. Prog Neurobiol 73:1–60

    Article  CAS  Google Scholar 

  23. Holmes GL, Gairsa JL, Chevassus-au-Louis N, Ben-Ari Y (1998) Consequences of neonatal seizures in the rat: morphological and behavioral effects. Ann Neurol 44:845–857

    Article  CAS  Google Scholar 

  24. Dube C, Chen K, Eghbal-Ahmadi M, Brunson K, Soltesz I, Baram TZ (2000) Prolonged febrile seizures in the immature rat model enhance hippocampal excitability long term. Ann Neurol 47:336–344

    Article  CAS  Google Scholar 

  25. Jensen FE, Applegate CD, Holtzman D, Belin TR, Burchfiel JL (1991) Epileptogenic effect of hypoxia in the immature rodent brain. Ann Neurol 29:629–637

    Article  CAS  Google Scholar 

  26. Hei Y, Chen R, Mao X, Wang J, Long Q, Liu W (2019) Neuregulin1 attenuates cognitive deficits and hippocampal CA1 neuronal apoptosis partly viaErbB4 receptor in a rat model of chronic cerebral hypoperfusion. Behav Brain Res 365:141–149

    Article  Google Scholar 

  27. Lau D, Vega-Saenz D, Miera EC, Contreras D, Ozaita A, Harvey M, Chow A, Noebels JL et al (2000) Impaired fast-spiking, suppressed cortical inhibition, and increased susceptibility to seizures in mice lacking Kv3.2 K+ channel proteins. J. Neurosci 20:9071–9085

    Article  CAS  Google Scholar 

  28. Nithianantharajah J, Hannan AJ (2006) Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nat Rev Neurosci 7:697–709

    Article  CAS  Google Scholar 

  29. Wang Y, Liang J, Chen L, Shen Y, Zhao J, Xu C, Wu X, Cheng H et al (2018) Pharmaco-genetic therapeutics targeting parvalbumin neurons attenuate temporal lobe epilepsy. Neurobiol Dis 117:149–160

    Article  CAS  Google Scholar 

Download references

Funding

This work was supported by the grants from the Research Fun of Ruijin Hospital North, School of Medicine, Shanghai Jiaotong University (No. 2016ZY11) and National Natural Science Foundation of China (No. 81701090) and Scientific Research Project of Sichuan Provincial Health Committee (No. 17PJ492)

Author information

Author notes

  1. Dong Liang and Fei Fan contributed equally to this work.

Authors and Affiliations

  1. Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin 2nd Road, Shanghai, China

    Dong Liang & Lan Hu

  2. Department of emergency, Ruijin Hospital North, School of Medicine, Shanghai Jiaotong University, 999 Xiwang Road, Jiading District, Shanghai, 201801, People’s Republic of China

    Dong Liang & Lan Hu

  3. Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-Er-Qiao Road, Chengdu, 610072, Sichuan Province, People’s Republic of China

    Fei Fan, Wei Ding, Yuan Fang, Bibo Lei & Mingqiang Zhang

Authors
  1. Dong Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fei Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wei Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuan Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lan Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bibo Lei
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mingqiang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conception: DL and MQZ; research design: MQZ, BBL; collection of data: YFL, YF; data analyses and interpretation: WD and DL; preparation of figures: FFL and YF; manuscript writing: MQZ and BBL.

Corresponding authors

Correspondence to Bibo Lei or Mingqiang Zhang.

Ethics declarations

The present study was approved by the Ethics Committee of Teaching Hospital of Chengdu University of T.C.M, Chengdu, China, and was conducted in accordance with the ARRIVE guidelines and the Guide for the Care and Use of Laboratory Animals from the National Institutes of Health (Bethesda, MD, USA).

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liang, D., Fan, F., Ding, W. et al. Increased Seizure Susceptibility for Rats Subject to Early Life Hypoxia Might Be Associated with Brain Dysfunction of NRG1-ErbB4 Signaling in Parvalbumin Interneurons. Mol Neurobiol 57, 5276–5285 (2020). https://doi.org/10.1007/s12035-020-02100-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-020-02100-3

Keywords

Search

Navigation