Metabolic Brain Disease

, Volume 34, Issue 1, pp 119–128 | Cite as

Excessive corticosterone induces excitotoxicity of hippocampal neurons and sensitivity of potassium channels via insulin-signaling pathway

  • Qingqing Xia
  • Hui Wang
  • Hongqiang Yin
  • Zhuo YangEmail author
Original Article


Corticosterone (CORT) is a kind of corticosteroid produced by cortex of adrenal glands. Hypothalamic–pituitary–adrenal (HPA) axis hyperfunction leads to excessive CORT, which is associated with depression. Few studies have investigated the role of CORT in voltage-gated ion channels and its upstream signaling pathway in central nervous system. In this study, we investigated the mechanism of excessive CORT resulting in brain impairment on voltage-gated ion channels, and its upstream signaling effectors in hippocampal CA1 neurons. The action potential (AP) and voltage-gated potassium currents were determined by using whole-cell patch-clamp. Insulin and CORT improved the neuronal excitability. Independent effects existed in transient potassium channel (IA) and delay rectifier potassium channel (IK). The inhibition of potassium currents, IA in our experiment, could increase neuronal excitability. CORT led to the excitotoxicity of hippocampal neurons via phosphatidylinositol 3 kinase (PI3K)-mediated insulin-signaling pathway. Therefore, the stimulation of excessive CORT induces excitotoxicity of hippocampal neurons and sensitivity of potassium channels via PI3K-mediated insulin-signaling pathway, which indicates one possible way of depression treatment.


Corticosterone Voltage-gated potassium channel Insulin-signaling pathway Hippocampal neurons 



This study was supported by grants from the National Natural Science Foundation of China (81571804, 81771979).

Author’s contribution

Zhuo Yang, Qingqing Xia and Hui Wang conceived the study and designed the experiments. Qingqing Xia performed all experiments and data analysis, wrote the manuscript and generated the figures. Hongqiang Yin provided the guidance of technique and data analysis. All authors have read and approved the manuscript.

Compliance with ethical standards

All animal experiments were approved by the Animal Research Ethics Committee, School of Medicine, Nankai University and were performed in accordance with the Animal Management Rules of the Ministry of Health of the People’s Republic of China.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

11011_2018_326_MOESM1_ESM.docx (213 kb)
ESM 1 (DOCX 212 kb)


  1. Aurand J-M et al (2016) Antidepressant-like activity of red wine phenolic extracts in repeated corticosterone-induced depression mice via BDNF/TrkB/CREB signaling pathway. BIO Web of Conferences 7:04009. CrossRefGoogle Scholar
  2. Brown ES, Varghese FP, McEwen BS (2004) Association of depression with medical illness: does cortisol play a role? Biol Psychiatry 55:1–9. CrossRefPubMedGoogle Scholar
  3. Buhl ES et al (2010) Treatment with an SSRI antidepressant restores hippocampo-hypothalamic corticosteroid feedback and reverses insulin resistance in low-birth-weight rats. Am J Phys Endocrinol Metab 298:E920–E929. CrossRefGoogle Scholar
  4. Cai S, Huang S, Hao W (2015) New hypothesis and treatment targets of depression: an integrated view of key findings. Neurosci Bull 31:61–74. CrossRefPubMedPubMedCentralGoogle Scholar
  5. Chen T, Yang J, Ren G, Yang Z, Zhang T (2013) Multi-walled carbon nanotube increases the excitability of hippocampal CA1 neurons through inhibition of potassium channels in rat's brain slices. Toxicol Lett 217:121–128. CrossRefPubMedGoogle Scholar
  6. Chen L, Dai J, Wang Z, Zhang H, Huang Y, Zhao Y (2014) Ginseng Total Saponins reverse corticosterone-induced changes in depression-like behavior and hippocampal plasticity-related proteins by interfering with GSK-3 beta -CREB signaling pathway Evid Based Complement Alternat Med : eCAM 2014:506735
  7. Chiu SL, Cline HT (2010) Insulin receptor signaling in the development of neuronal structure and function. Neural Dev 5:18. CrossRefGoogle Scholar
  8. Chiu SL, Chen CM, Cline HT (2008) Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo. Neuron 58:708–719. CrossRefPubMedPubMedCentralGoogle Scholar
  9. Dai W, Yang J, Chen T, Yang Z (2014) Protective effects of bexarotene against amyloid-beta25-35-induced dysfunction in hippocampal neurons through the insulin signaling pathway. Neurodegener Dis 14:77–84. CrossRefPubMedGoogle Scholar
  10. Dobarro M, Orejana L, Aguirre N, Ramirez MJ (2013) Propranolol reduces cognitive deficits, amyloid beta levels, tau phosphorylation and insulin resistance in response to chronic corticosterone administration. Int J Neuropsychopharmacol 16:1351–1360. CrossRefPubMedGoogle Scholar
  11. Gold PW, Machado-Vieira R, Pavlatou MG (2015) Clinical and biochemical manifestations of depression: relation to the neurobiology of stress. Neural Plasticity 2015:1–11. CrossRefGoogle Scholar
  12. Grinevich V, Seeburg PH, Schwarz MK, Jezova D (2012) Homer 1 – a new player linking the hypothalamic-pituitary-adrenal axis activity to depression and anxiety. Endocr Regul 46:153–159. CrossRefPubMedGoogle Scholar
  13. Johnson SA, Fournier NM, Kalynchuk LE (2006) Effect of different doses of corticosterone on depression-like behavior and HPA axis responses to a novel stressor. Behav Brain Res 168:280–288. CrossRefPubMedGoogle Scholar
  14. Joseph A, Turrigiano GG (2017) All for one but not one for all: excitatory synaptic scaling and intrinsic excitability are Coregulated by CaMKIV, whereas inhibitory synaptic scaling is under independent control. J Neurosci 37:6778–6785. CrossRefPubMedPubMedCentralGoogle Scholar
  15. Karst H, Berger S, Turiault M, Tronche F, Schutz G, Joels M (2005) Mineralocorticoid receptors are indispensable for nongenomic modulation of hippocampal glutamate transmission by corticosterone. Proc Natl Acad Sci U S A 102:19204–19207. CrossRefPubMedPubMedCentralGoogle Scholar
  16. Kinlein SA, Shahanoor Z, Romeo RD, Karatsoreos IN (2017) Chronic corticosterone treatment during adolescence has significant effects on metabolism and skeletal development in male C57BL6/N mice. Endocrinology 158:2239–2254. CrossRefPubMedPubMedCentralGoogle Scholar
  17. Kudryashova IV (2015) Neurodegenerative changes in depression: excitotoxicity or a deficit of trophic factors? Neurochem J 9:1–7. CrossRefGoogle Scholar
  18. Larimore J et al (2017) Dysbindin deficiency modifies the expression of GABA neuron and ion permeation transcripts in the developing Hippocampus. Front Genet 8:14. CrossRefGoogle Scholar
  19. Lee B, Sur B, Shim I, Lee H, Hahm DH (2015) Angelica gigas ameliorate depression-like symptoms in rats following chronic corticosterone injection. BMC Complement Altern Med 15:210. CrossRefPubMedPubMedCentralGoogle Scholar
  20. Liu DH et al (2014) Voltage dependent Potassium Channel remodeling in murine intestinal smooth muscle hypertrophy induced by partial obstruction. PLoS One 9:12. CrossRefGoogle Scholar
  21. Lucassen PJ et al (2014) Neuropathology of stress. Acta Neuropathol 127:109–135. CrossRefPubMedGoogle Scholar
  22. Murray F, Smith DW, Hutson PH (2008) Chronic low dose corticosterone exposure decreased hippocampal cell proliferation, volume and induced anxiety and depression like behaviours in mice. Eur J Pharmacol 583:115–127. CrossRefPubMedGoogle Scholar
  23. Osmanovic J, Plaschke K, Salkovic-Petrisic M, Gruenblatt E, Riederer P, Hoyer S (2010) Chronic exogenous corticosterone administration generates an insulin-resistant brain state in rats stress-the international. Journal on the Biology of Stress 13:123–131. CrossRefGoogle Scholar
  24. Piroli GG, Grillo CA, Reznikov LR, Adams S, McEwen BS, Charron MJ, Reagan LP (2007) Corticosterone impairs insulin-stimulated translocation of GLUT4 in the rat hippocampus. Neuroendocrinology 85:71–80. CrossRefPubMedGoogle Scholar
  25. Russell AL, Tasker JG, Lucion AB, Fiedler J, Munhoz CD, Wu TJ, Deak T (2018) Factors promoting vulnerability to dysregulated stress reactivity and stress-related disease. J Neuroendocrinol:e12641.
  26. Schroder W, Hinterkeuser S, Seifert G, Schramm J, Jabs R, Wilkin GP, Steinhauser C (2000) Functional and molecular properties of human astrocytes in acute hippocampal slices obtained from patients with temporal lobe epilepsy. Epilepsia 41:S181–S184. CrossRefPubMedGoogle Scholar
  27. Scott LV, Dinan TG (1998) Vasopressin and the regulation of hypothalamic-pituitary-adrenal axis function: implications for the pathophysiology of depression. Life Sci 62:1985–1998CrossRefGoogle Scholar
  28. Solas M, Gerenu G, Gil-Bea FJ, Ramirez MJ (2013) Mineralocorticoid receptor activation induces insulin resistance through c-Jun N-terminal kinases in response to chronic corticosterone: cognitive implications. J Neuroendocrinol 25:350–356. CrossRefPubMedGoogle Scholar
  29. Stranahan AM, Arumugam TV, Cutler RG, Lee K, Egan JM, Mattson MP (2008) Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons. Nat Neurosci 11:309–317. CrossRefPubMedPubMedCentralGoogle Scholar
  30. Teramoto N (2006) Physiological roles of ATP-sensitive K+ channels in smooth muscle. J Physiol 572:617–624. CrossRefPubMedPubMedCentralGoogle Scholar
  31. Ulloa JL et al (2010) Comparison of the antidepressant sertraline on differential depression-like behaviors elicited by restraint stress and repeated corticosterone administration. Pharmacol Biochem Behav 97:213–221. CrossRefPubMedGoogle Scholar
  32. Wieczorek L, Fish EW, O'Leary-Moore SK, Parnell SE, Sulik KK (2015) Hypothalamic-pituitary-adrenal axis and behavioral dysfunction following early binge-like prenatal alcohol exposure in mice. Alcohol 49:207–217. CrossRefPubMedPubMedCentralGoogle Scholar
  33. Xiao X, Zhang H, Wang H, Li Q, Zhang T (2017) Neuroprotective effect of amantadine on corticosterone-induced abnormal glutamatergic synaptic transmission of CA3-CA1 pathway in rat's hippocampal slices 71
  34. Xu P, Xu J, Li Z, Yang Z (2012) Expression of TRPC6 in renal cortex and hippocampus of mouse during postnatal development. PLoS One 7:e38503. CrossRefPubMedPubMedCentralGoogle Scholar
  35. Yao JJ, Gao XF, Chow CW, Zhan XQ, Hu CL, Mei YA (2012) Neuritin activates insulin receptor pathway to up-regulate Kv4.2-mediated transient outward K+ current in rat cerebellar granule neurons. J Biol Chem 287:41534–41545. CrossRefPubMedPubMedCentralGoogle Scholar
  36. Yao JJ, Sun J, Zhao QR, Wang CY, Mei YA (2013) Neuregulin-1/ErbB4 signaling regulates Kv4.2-mediated transient outward K+ current through the Akt/mTOR pathway. Am J Physiol Cell Physiol 305:C197–C206. CrossRefPubMedPubMedCentralGoogle Scholar
  37. Yasui S et al (2008) Insulin activates ATP-sensitive potassium channels via phosphatidylinositol 3-kinase in cultured vascular smooth muscle cells. J Vasc Res 45:233–243. CrossRefPubMedGoogle Scholar
  38. Yin H, Wang H, Zhang H, Gao N, Zhang T, Yang Z (2017) Resveratrol attenuates Aβ-induced early hippocampal neuron excitability impairment via recovery of function of potassium channels. Neurotox Res.
  39. Zhang L, McBain CJ (1995) Potassium conductances underlying repolarization and after-hyperpolarization in rat CA1 hippocampal interneurones. J Physiol 488(Pt 3):661–672CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.College of Medicine, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials for Ministry of EducationNankai UniversityTianjinChina
  2. 2.College of Life SciencesNankai UniversityTianjinChina

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