Skip to main content

Advertisement

SpringerLink
Log in

Transient Receptor Potential Vanilloid 6 Modulates Aberrant Axonal Sprouting in a Mouse Model of Pilocarpine-Induced Epilepsy

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Transient receptor potential vanilloid 6 (TRPV6) is a highly selective calcium-ion channel that belongs to the TRPV family. TRPV6 is widely distributed in the brain, but its role in neurological diseases such as epilepsy remains unknown. Here, we report for the first time that TRPV6 expression is upregulated in the hippocampus of a pilocarpine-induced status epilepticus model, mainly in the suprapyramidal bundle of the mossy fiber (MF) projection of the hippocampal CA3 regions. We found that TRPV6 overexpression via viral vector transduction attenuated abnormal MF sprouting (MFS), whereas TRPV6 knockdown aggravated the development of MFS and the incidence of recurrent seizures during epileptogenic progression. In the in vitro experiments, our results showed that modulation of TRPV6 expression resulted in a change in axonal formation in cultured hippocampal neurons. In addition, we found that TRPV6 was implicated in the regulation of Akt-glycogen synthase kinase-3-β activity, which is closely related to the cellular mechanism of axonal outgrowth. Therefore, these findings suggest that TRPV6 may regulate the formation of aberrant synaptic circuits during epileptogenesis.

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

Similar content being viewed by others

Data Availability

Data will be made available on reasonable request.

References

  1. Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, Engel J Jr, Forsgren L et al (2014) ILAE official report: a practical clinical definition of epilepsy. Epilepsia 55(4):475–482. https://doi.org/10.1111/epi.12550

    Article  PubMed  Google Scholar 

  2. Bertram EH (2009) Temporal lobe epilepsy: where do the seizures really begin? Epilepsy Behav 14(Suppl 1):32–37. https://doi.org/10.1016/j.yebeh.2008.09.017

    Article  PubMed  Google Scholar 

  3. Loscher W, Schmidt D (2004) New horizons in the development of antiepileptic drugs: the search for new targets. Epilepsy Res 60(2–3):77–159. https://doi.org/10.1016/j.eplepsyres.2004.06.004

    Article  CAS  PubMed  Google Scholar 

  4. Loscher W, Schmidt D (2011) Modern antiepileptic drug development has failed to deliver: ways out of the current dilemma. Epilepsia 52(4):657–678. https://doi.org/10.1111/j.1528-1167.2011.03024.x

    Article  PubMed  Google Scholar 

  5. Patel DC, Wilcox KS, Metcalf CS (2017) Novel targets for developing antiseizure and potentially, antiepileptogenic drugs. Epilepsy Curr 17(5):293–298. https://doi.org/10.5698/1535-7597.17.5.293

    Article  PubMed  PubMed Central  Google Scholar 

  6. Dalby NO, Mody I (2001) The process of epileptogenesis: a pathophysiological approach. Curr Opin Neurol 14(2):187–192. https://doi.org/10.1097/00019052-200104000-00009

    Article  CAS  PubMed  Google Scholar 

  7. Hendricks WD, Westbrook GL, Schnell E (2019) Early detonation by sprouted mossy fibers enables aberrant dentate network activity. Proc Natl Acad Sci U S A 116(22):10994–10999. https://doi.org/10.1073/pnas.1821227116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Cavarsan CF, Malheiros J, Hamani C, Najm I, Covolan L (2018) Is mossy fiber sprouting a potential therapeutic target for epilepsy? Front Neurol 9:1023. https://doi.org/10.3389/fneur.2018.01023

    Article  PubMed  PubMed Central  Google Scholar 

  9. Clapham DE, Julius D, Montell C, Schultz G (2005) International Union of Pharmacology. XLIX. Nomenclature and structure-function relationships of transient receptor potential channels. Pharmacol Rev 57(4):427–450. https://doi.org/10.1124/pr.57.4.6

    Article  CAS  PubMed  Google Scholar 

  10. Lee K, Jo YY, Chung G, Jung JH, Kim YH, Park CK (2021) Functional importance of transient receptor potential (TRP) channels in neurological disorders. Front Cell Dev Biol 9:611773. https://doi.org/10.3389/fcell.2021.611773

    Article  PubMed  PubMed Central  Google Scholar 

  11. Saffarzadeh F, Eslamizade MJ, Ghadiri T, Modarres Mousavi SM, Hadjighassem M, Gorji A (2015) Effects of TRPV1 on the hippocampal synaptic plasticity in the epileptic rat brain. Synapse 69(7):375–383. https://doi.org/10.1002/syn.21825

    Article  CAS  PubMed  Google Scholar 

  12. Naziroglu M, Ovey IS (2015) Involvement of apoptosis and calcium accumulation through TRPV1 channels in neurobiology of epilepsy. Neuroscience 293:55–66. https://doi.org/10.1016/j.neuroscience.2015.02.041

    Article  CAS  PubMed  Google Scholar 

  13. Muller M, Pape HC, Speckmann EJ, Gorji A (2006) Effect of eugenol on spreading depression and epileptiform discharges in rat neocortical and hippocampal tissues. Neuroscience 140(2):743–751. https://doi.org/10.1016/j.neuroscience.2006.02.036

    Article  CAS  PubMed  Google Scholar 

  14. Wang Z, Zhou L, An D, Xu W, Wu C, Sha S, Li Y, Zhu Y et al (2019) TRPV4-induced inflammatory response is involved in neuronal death in pilocarpine model of temporal lobe epilepsy in mice. Cell Death Dis 10(6):386. https://doi.org/10.1038/s41419-019-1612-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kumar S, Singh O, Singh U, Goswami C, Singru PS (2018) Transient receptor potential vanilloid 1–6 (Trpv1-6) gene expression in the mouse brain during estrous cycle. Brain Res 1701:161–170. https://doi.org/10.1016/j.brainres.2018.09.005

    Article  CAS  PubMed  Google Scholar 

  16. Nijenhuis T, Hoenderop JG, van der Kemp AW, Bindels RJ (2003) Localization and regulation of the epithelial Ca2+ channel TRPV6 in the kidney. J Am Soc Nephrol 14(11):2731–2740. https://doi.org/10.1097/01.asn.0000094081.78893.e8

    Article  CAS  PubMed  Google Scholar 

  17. Kumar S, Singh U, Singh O, Goswami C, Singru PS (2017) Transient receptor potential vanilloid 6 (TRPV6) in the mouse brain: Distribution and estrous cycle-related changes in the hypothalamus. Neuroscience 344:204–216. https://doi.org/10.1016/j.neuroscience.2016.12.025

    Article  CAS  PubMed  Google Scholar 

  18. Park SY, Yoo YM, Jung EM, Jeung EB (2020) The effect of steroid hormone on the expression of the calcium-processing proteins in the immature female rat brain. J Chem Neuroanat 105:101767. https://doi.org/10.1016/j.jchemneu.2020.101767

    Article  CAS  PubMed  Google Scholar 

  19. Jeong KH, Cho KO, Lee MY, Kim SY, Kim WJ (2021) Vascular endothelial growth factor receptor-3 regulates astroglial glutamate transporter-1 expression via mTOR activation in reactive astrocytes following pilocarpine-induced status epilepticus. Glia 69(2):296–309. https://doi.org/10.1002/glia.23897

    Article  CAS  PubMed  Google Scholar 

  20. Racine RJ (1972) Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol 32(3):281–294. https://doi.org/10.1016/0013-4694(72)90177-0

    Article  CAS  PubMed  Google Scholar 

  21. Kim JC, Hwang SN, Kim SY (2020) Alteration of Gene Associated with Retinoid-interferon-induced Mortality-19-expressing Cell Types in the Mouse Hippocampus Following Pilocarpine-induced Status Epilepticus. Neuroscience 425:49–58. https://doi.org/10.1016/j.neuroscience.2019.11.015

    Article  CAS  PubMed  Google Scholar 

  22. Kourdougli N, Varpula S, Chazal G, Rivera C (2015) Detrimental effect of post Status Epilepticus treatment with ROCK inhibitor Y-27632 in a pilocarpine model of temporal lobe epilepsy. Front Cell Neurosci 9:413. https://doi.org/10.3389/fncel.2015.00413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bertoldi ML, Zalosnik MI, Fabio MC, Aja S, Roth GA, Ronnett GV, Degano AL (2019) MeCP2 deficiency disrupts kainate-induced presynaptic plasticity in the mossy fiber projections in the hippocampus. Front Cell Neurosci 13:286. https://doi.org/10.3389/fncel.2019.00286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Cho YJ, Kim H, Kim WJ, Chung S, Kim YH, Cho I, Lee BI, Heo K (2017) Trafficking patterns of NMDA and GABA(A) receptors in a Mg(2+)-free cultured hippocampal neuron model of status epilepticus. Epilepsy Res 136:143–148. https://doi.org/10.1016/j.eplepsyres.2017.08.003

    Article  CAS  PubMed  Google Scholar 

  25. Goodkin HP, Yeh JL, Kapur J (2005) Status epilepticus increases the intracellular accumulation of GABAA receptors. J Neurosci 25(23):5511–5520. https://doi.org/10.1523/JNEUROSCI.0900-05.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kimura Y, Fujita Y, Shibata K, Mori M, Yamashita T (2013) Sigma-1 receptor enhances neurite elongation of cerebellar granule neurons via TrkB signaling. PLoS ONE 8(10):e75760. https://doi.org/10.1371/journal.pone.0075760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Koyama R, Ikegaya Y (2004) Mossy fiber sprouting as a potential therapeutic target for epilepsy. Curr Neurovasc Res 1(1):3–10. https://doi.org/10.2174/1567202043480242

    Article  PubMed  Google Scholar 

  28. Yoshimura T, Arimura N, Kaibuchi K (2006) Signaling networks in neuronal polarization. J Neurosci 26(42):10626–10630. https://doi.org/10.1523/JNEUROSCI.3824-06.2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Jiang H, Guo W, Liang X, Rao Y (2005) Both the establishment and the maintenance of neuronal polarity require active mechanisms: critical roles of GSK-3beta and its upstream regulators. Cell 120(1):123–135. https://doi.org/10.1016/j.cell.2004.12.033

    Article  CAS  PubMed  Google Scholar 

  30. Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA (1995) Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378(6559):785–789. https://doi.org/10.1038/378785a0

    Article  CAS  PubMed  Google Scholar 

  31. Hainmueller T, Bartos M (2020) Dentate gyrus circuits for encoding, retrieval and discrimination of episodic memories. Nat Rev Neurosci 21(3):153–168. https://doi.org/10.1038/s41583-019-0260-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Nakahara S, Adachi M, Ito H, Matsumoto M, Tajinda K, van Erp TGM (2018) Hippocampal pathophysiology: commonality shared by temporal lobe epilepsy and psychiatric disorders. Neurosci J 2018:4852359. https://doi.org/10.1155/2018/4852359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Koyama R, Ikegaya Y (2018) The molecular and cellular mechanisms of axon guidance in mossy fiber sprouting. Front Neurol 9:382. https://doi.org/10.3389/fneur.2018.00382

    Article  PubMed  PubMed Central  Google Scholar 

  34. Romer B, Krebs J, Overall RW, Fabel K, Babu H, Overstreet-Wadiche L, Brandt MD, Williams RW et al (2011) Adult hippocampal neurogenesis and plasticity in the infrapyramidal bundle of the mossy fiber projection: I. Co-regulation by activity. Front Neurosci 5:107. https://doi.org/10.3389/fnins.2011.00107

    Article  PubMed  PubMed Central  Google Scholar 

  35. Kaidanovich-Beilin O, Woodgett JR (2011) GSK-3: functional insights from cell biology and animal models. Front Mol Neurosci 4:40. https://doi.org/10.3389/fnmol.2011.00040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Craig AM, Banker G (1994) Neuronal polarity. Annu Rev Neurosci 17:267–310. https://doi.org/10.1146/annurev.ne.17.030194.001411

    Article  CAS  PubMed  Google Scholar 

  37. Li Z, Meng Z, Lu J, Chen FM, Wong WT, Tse G, Zheng C, Keung W et al (2018) TRPV6 protects ER stress-induced apoptosis via ATF6alpha-TRPV6-JNK pathway in human embryonic stem cell-derived cardiomyocytes. J Mol Cell Cardiol 120:1–11. https://doi.org/10.1016/j.yjmcc.2018.05.008

    Article  CAS  PubMed  Google Scholar 

  38. Ma J, Zhu L, Zhou Z, Song T, Yang L, Yan X, Chen A, Ye TW (2021) The calcium channel TRPV6 is a novel regulator of RANKL-induced osteoclastic differentiation and bone absorption activity through the IGF-PI3K-AKT pathway. Cell Prolif 54(1):e12955. https://doi.org/10.1111/cpr.12955

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2021R1I1A1A01045520).

Funding

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2021R1I1A1A01045520).

Author information

Authors and Affiliations

  1. Epilepsy Research Institute, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea

    Kyoung Hoon Jeong

  2. Department of Neurology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea

    Jing Zhu & Soojin Park

  3. Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, 06273, Republic of Korea

    Won-Joo Kim

Authors
  1. Kyoung Hoon Jeong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Soojin Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Won-Joo Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

K.H.J. contributed to study conceptualization, designed and performed the experiments, analyzed the data, contributed to funding acquisition, and wrote the manuscript. J.Z. and S.J.P. supported the experiments and data analysis. K.H.J. and W.J.K. contributed to project administration. All authors have consented to the submission of this manuscript.

Corresponding authors

Correspondence to Kyoung Hoon Jeong or Won-Joo Kim.

Ethics declarations

Ethics Approval

All procedures were approved by the Institutional Committee for the Care and Use of Laboratory Animals at Yonsei University Health System.

Consent for Publication

This manuscript has not been published or presented elsewhere in part or entirety and is not under consideration by another journal. All the authors have read and approved the final version of the manuscript.

Competing Interests

The authors have no relevant financial or nonfinancial interests to disclose.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 612 KB)

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

Jeong, K.H., Zhu, J., Park, S. et al. Transient Receptor Potential Vanilloid 6 Modulates Aberrant Axonal Sprouting in a Mouse Model of Pilocarpine-Induced Epilepsy. Mol Neurobiol 61, 2839–2853 (2024). https://doi.org/10.1007/s12035-023-03748-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-023-03748-3

Keywords

Search

Navigation