Skip to main content

Advertisement

SpringerLink
Log in

Activation of ephrinb1/EPHB2/MAP-2/NMDAR Mediates Hippocampal Neurogenesis Promoted by Transcranial Direct Current Stimulation in Cerebral-Ischemic Mice

  • Original Paper
  • Published:
NeuroMolecular Medicine Aims and scope Submit manuscript

Abstract

tDCS, a new, safe, non-invasive physical therapy method, is often used in motor dysfunction rehabilitation. However, the effects and underlying mechanisms of tDCS on hippocampal neurogenesis after cerebral ischemia (CI) are still unclear. This study aimed to investigate the promotive effect and mechanism of repetitive anodal-tDCS on hippocampal neurogenesis after CI in mice. The CI model in mice was established using bilateral common carotid artery occlusion (BCCAO). The pathological changes in the hippocampal CA1 region and cognitive function were assessed by hematoxylin and eosin staining and Morris water maze test, respectively. Hippocampal neurogenesis was observed by immunofluorescence staining. The levels of expression of ephrinb1, EPHB2, MAP-2, and NMDAR in the hippocampi were analyzed by qRT-PCR and Western blotting. Compared with the sham mice, the model mice showed significant neuronal damage in the hippocampal CA1 region (P < 0.01), cognitive dysfunction (P < 0.01), and endogenous hippocampal neurogenesis (P < 0.01). These results suggested that the CI model was successfully established, and that CI could promote endogenous hippocampal neurogenesis, but this hippocampal neurogenesis was unable to recover cognitive dysfunction. Compared with the model mice, the tDCS mice had ameliorated pathological damage in the CA1 region (P < 0.01), improved cognitive function (P < 0.01), increased hippocampal neurogenesis (P < 0.01), and increased mRNA and protein expression of ephrinb1, EPHB2, MAP-2, and NMDAR (P < 0.05). Repetitive anodal-tDCS can promote hippocampal neurogenesis and improve cognitive function in CI mice. The effect may be related to the activation of the ephrinb1/EPHB2/MAP-2/NMDAR signaling pathway.

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

Similar content being viewed by others

Abbreviations

BCCAO:

Bilateral common carotid artery occlusion

BrdU:

5-Bromo-2′-deoxyuridine

CI:

Cerebral ischemia

DCX:

Doublecortin

DG:

Dentate gyrus

Eph:

Erythropoietin-producing hepatocellular

H&E:

Hematoxylin and eosin

MAP-2:

Microtubule-associated protein 2

MWM:

Morris water maze

NMDA:

N-Methyl-d-aspartic acid

NSC:

Neural stem cells

SVZ:

Subventricular zone

tDCS:

Transcranial direct current stimulation

TMS:

Transcranial magnetic stimulation

References

  • Belopasova, A. V., Dobrynina, L. A., Kadykov, A. S., Berdnikovich, E. S., & Tsypushtanova, M. M. (2020). Noninvasive brain stimulation in the rehabilitation of patients with post-stroke aphasia. Zhurnal Nevrologii i Psikhiatrii Imeni S.S. Korsakova, 120, 23–28.

    Article  CAS  Google Scholar 

  • Brittain, J. S., & Cagnan, H. (2018). Recent trends in the use of electrical neuromodulation in Parkinson’s disease. Current Behavioral Neuroscience Reports, 5, 170–178.

    Article  Google Scholar 

  • Chen, L., Song, D., Chen, B., Yang, X., & Cheng, O. (2020). Activation of liver X receptor promotes hippocampal neurogenesis and improves long-term cognitive function recovery in acute cerebral ischemia-reperfusion mice. Journal of Neurochemistry, 154, 205–217.

    Article  CAS  Google Scholar 

  • Chumley, M. J., Catchpole, T., Silvany, R. E., Kernie, S. G., & Henkemeyer, M. (2007). EphB receptors regulate stem/progenitor cell proliferation, migration, and polarity during hippocampal neurogenesis. Journal of Neuroscience, 27, 13481–13490.

    Article  CAS  Google Scholar 

  • Dundas, J. E., Thickbroom, G. W., & Mastaglia, F. L. (2007). Perception of comfort during transcranial DC stimulation: Effect of NaCl solution concentration applied to sponge electrodes. Clinical Neurophysiology, 118, 1166–1170.

    Article  CAS  Google Scholar 

  • Farzanehfar, P. (2018). Comparative review of adult midbrain and striatum neurogenesis with classical neurogenesis. Neuroscience Research, 134, 1–9.

    Article  Google Scholar 

  • Gong, J., Körner, R., Gaitanos, L., & Klein, R. (2016). Exosomes mediate cell contact-independent ephrin-Eph signaling during axon guidance. Journal of Cell Biology, 214, 35–44.

    Article  CAS  Google Scholar 

  • Hanamura, K., Washburn, H. R., Sheffler-Collins, S. I., Xia, N. L., Henderson, N., & Tillu, D. V. (2017). Extracellular phosphorylation of a receptor tyrosine kinase controls synaptic localization of NMDA receptors and regulates pathological pain. PLoS Biology, 15, e2002457.

    Article  Google Scholar 

  • Heit, J. J., & Wintermark, M. (2018). New developments in clinical ischemic stroke prevention and treatment and their imaging implications. Journal of Cerebral Blood Flow and Metabolism, 38, 1533–1550.

    Article  Google Scholar 

  • Huan, X., Oumei, C., Hongmei, Q., Junxia, Y., Xiaojiao, M., & Qingsong, J. (2020). PDE9 inhibition promotes proliferation of neural stem cells via cGMP-PKG pathway following oxygen-glucose deprivation/reoxygenation injury in vitro. Neurochemistry International, 133, 104630.

    Article  CAS  Google Scholar 

  • Lefaucheur, J. P., Antal, A., Ayache, S. S., Benninger, D. H., Brunelin, J., & Cogiamanian, F. (2016). Evidence-based guidelines on the therapeutic use of transcranial direct current stimulation (tDCS). Clinical Neurophysiology, 128, 56–92.

    Article  Google Scholar 

  • Liu, C. S., Rau, A., Gallagher, D., Rajji, T. K., Lanctôt, K. L., & Herrmann, N. (2017). Using transcranial direct current stimulation to treat symptoms in mild cognitive impairment and Alzheimer’s disease. Neurodegenerative Disease Management, 7, 317–329.

    Article  Google Scholar 

  • Maekawa, M., Namba, T., Suzuki, E., Yuasa, S., Kohsaka, S., & Uchino, S. (2009). NMDA receptor antagonist memantine promotes cell proliferation and production of mature granule neurons in the adult hippocampus. Neuroscience Research, 63, 259–266.

    Article  CAS  Google Scholar 

  • Monai, H., & Hirase, H. (2016). Astrocytic calcium activation in a mouse model of tDCS-Extended discussion. Neurogenesis (Austin), 3, e1240055.

    Article  Google Scholar 

  • Mortensen, J., Figlewski, K., & Andersen, H. (2016). Combined transcranial direct current stimulation and home-based occupational therapy for upper limb motor impairment following intracerebral hemorrhage: A double-blind randomized controlled trial. Disability and Rehabilitation, 38, 637–643.

    Article  Google Scholar 

  • Nolt, M. J., Lin, Y., Hruska, M., Murphy, J., Sheffler-Colins, S. I., & Kayser, M. S. (2011). EphB controls NMDA receptor function and synaptic targeting in a subunit-specific manner. Journal of Neuroscience, 31, 5353–5364.

    Article  CAS  Google Scholar 

  • Pikhovych, A., Stolberg, N. P., & Jessica, F. L. (2016). Transcranial direct current stimulation modulates neurogenesis and microglia activation in the mouse brain. Stem Cells International. https://doi.org/10.1155/2016/2715196.

    Article  PubMed  PubMed Central  Google Scholar 

  • Klein, R. (2012). Eph/ephrin signalling during development. Development, 139, 4105–4109.

    Article  CAS  Google Scholar 

  • Ramírez, E., Mendieta, L., Flores, G., & Limón, I. D. (2016). Neurogenesis and morphological-neural alterations closely related to amyloid β-peptide (25–35)-induced memory impairment in male rats. Neuropeptides, 67, 9–19.

    Article  Google Scholar 

  • Razza, L. B., Palumbo, P., Moffa, A. H., Carvalho, A. F., Solmi, M., & Loo, C. K. (2020). A systematic review and meta-analysis on the effects of transcranial direct current stimulation in depressive episodes. Depression and Anxiety. https://doi.org/10.1002/da.23004.

    Article  PubMed  Google Scholar 

  • Sánchez-Farías, N., & Candal, E. (2015). Doublecortin is widely expressed in the developing and adult retina of sharks. Experimental Eye Research, 134, 90–100.

    Article  Google Scholar 

  • Sánchez, C., Díaz-Nido, J., & Avila, J. (2000). Phosphorylation of microtubule-associated protein 2 (MAP2) and its relevance for the regulation of the neuronal cytoskeleton function. Progress in Neurobiology, 61, 133–168.

    Article  Google Scholar 

  • Shi, X. D., Sun, K., Hu, R., Liu, X. Y., Hu, Q. M., & Sun, X. Y. (2016). Blocking the interaction between ephb2 and addls by a small peptide rescues impaired synaptic plasticity and memory deficits in a mouse model of Alzheimer’s disease. Journal of Neuroscience, 2016(36), 11959–11973.

    Article  Google Scholar 

  • Tian, L., Nie, H., Zhang, Y., Chen, Y., Peng, Z., & Cai, M. (2014). Recombinant humain-1 promotes neurogenesis and facilitates cognitive recovery following cerebral ischemia in mice. Neuropharmacology, 77, 453–464.

    Article  CAS  Google Scholar 

  • Toda, T., & Gage, F. H. (2018). Review: Adult neurogenesis contributes to hippocampal plasticity. Cell and Tissue Research, 373, 693–709.

    Article  Google Scholar 

  • Wegner, F., Kraft, R., Busse, K., Schaarschmidt, G., Wolfgang, H., & Schwarz, S. C. (2010). Glutamate receptor properties of human mesencephalic neural progenitor cells: NMDA enhances dopaminergic neurogenesis in vitro. Journal of Neurochemistry, 111, 204–216.

    Article  Google Scholar 

  • Wei, L., Ren, Q., Zhang, Y., & Wang, J. (2017). Effects of hyperbaric oxygen and nerve growth factor on the long-term neural behavior of neonatal rats with hypoxic ischemic brain damage. Acta Cirúrgica Brasileira, 32, 270–279.

    Article  Google Scholar 

  • Yu, X., Li, Y., Wen, H., Zhang, Y., & Tian, X. (2015). Intensity-dependent effects of repetitive anodal transcranial direct current stimulation on learning and memory in a rat model of Alzheimer’s disease. Neurobiology of Learning and Memory, 123, 168–178.

    Article  Google Scholar 

  • Zhen, G., & Doré, S. (2007). Optimized protocol to reduce variable outcomes for the bilateral common carotid artery occlusion model in mice. Journal of Neuroscience Methods, 166, 73–80.

    Article  Google Scholar 

Download references

Funding

This study was supported by the National Natural Science Foundation of China The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grants from the National Natural Science Foundation of China (Nos. 81871002, 81471334, 81100981), Pharmacy College of Chongqing Medical University (Nos. YXY2019SDTR01), and the Natural Science Foundation of Chongqing (No. cstc2017jcyjAX0211).

Author information

Author notes

  1. Xiaojiao Ma and Oumei Cheng should be considered joint first author.

Authors and Affiliations

  1. Department of Pharmacology, College of Pharmacy, Chongqing Key Lab of Biochemistry and Molecular Pharmacology, Chongqing Key Lab Drug Metabolism, Chongqing Medical University, No. 1 Yixueyuan Road, Chongqing, 400016, China

    Xiaojiao Ma, Qingsong Jiang, Junxia Yang, Huan Xiao & Hongmei Qiu

  2. Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China

    Oumei Cheng

Authors
  1. Xiaojiao Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Oumei Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qingsong Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Junxia Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Huan Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hongmei Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

HMQ, OMC and QSJ conceived and designed the experiment. XJM and HX performed the experiments. XJM, HX, and JXY analyzed the data. XJM and HMQ wrote the manuscript.

Corresponding author

Correspondence to Hongmei Qiu.

Ethics declarations

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

Ma, X., Cheng, O., Jiang, Q. et al. Activation of ephrinb1/EPHB2/MAP-2/NMDAR Mediates Hippocampal Neurogenesis Promoted by Transcranial Direct Current Stimulation in Cerebral-Ischemic Mice. Neuromol Med 23, 521–530 (2021). https://doi.org/10.1007/s12017-021-08654-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12017-021-08654-2

Keywords

Search

Navigation