Skip to main content
SpringerLink
Log in

Over-expression of 5-HT6 Receptor and Activated Jab-1/p-c-Jun Play Important Roles in Pilocarpine-Induced Seizures and Learning-Memory Impairment

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Cognitive impairment is a common comorbidity in patients with temporal lobe epilepsy (TLE) that severely affects patients’ quality of life. Also, serotonin 5-hydroxytryptamine 6 (5-HT6) receptor plays an important role in cognition. This study aimed to investigate effects of 5-HT6 receptor on learning-memory capacities in epileptic rats. Total of 36 adult Sprague-Dawley (SD) rats were divided into vehicle (n = 6) and epileptic group (n = 30). Status epilepticus (SE) was induced via systemic injection of pilocarpine. Epileptic group was sub-divided into vehicle, 10, 20, and 30 μg SB-271046 groups, six mice per group. Learning-memory performance of rats was evaluated by using Y maze and Morris water maze test. 5-HT6 receptor expression was examined using immunostaining and Western blot. The other six rats were used to make epileptic model and Jab-1/p-c-Jun were detected. Results showed that frequency of spontaneous recurrent seizures (SRSs) was significantly decreased in pilocarpine-induced epileptic rats that treated with SB-271046. Alternation rate and new arm percentage were decreased in epileptic rats compared to control. The 5-day mean latency was prolonged in epileptic rats compared to control rats. During retention stage, mean latency, number of target crossings, and percentage of time spent in target zone were decreased in epileptic rats, but not in those treated with SB-271046. The number of apoptotic neurons was significantly increased in epileptic rats, which was decreased by SB-271046. 5-HT6 expression was significantly increased in hippocampus and cortex following recurrent seizures. Jab-1 level was decreased after SB-271046 administration. p-c-Jun level was elevated in epileptic rats and decreased in a dose-dependent manner after the SB-271046 administration. In conclusion, the over-expression of 5-HT6 receptor and activated Jab-1/p-c-Jun plays an important role in pilocarpine-induced seizures and learning-memory impairment.

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

Similar content being viewed by others

References

  • Berg AT (2011) Epilepsy, cognition, and behavior: the clinical picture. Epilepsia 52(Suppl 1):7–12

    Article  PubMed  PubMed Central  Google Scholar 

  • Blumcke I, Spreafico R, Haaker G, Coras R, Kobow K, Bien CG, Pfafflin M, Elger C, Widman G, Schramm J, Becker A, Braun KP, Leijten F (2017) Histopathological findings in brain tissue obtained during epilepsy surgery. N Engl J Med 377:1648–1656

    Article  PubMed  Google Scholar 

  • Brouard JT, Schweimer JV, Houlton R, Burnham KE, Queree P, Sharp T (2015) Pharmacological evidence for 5-HT6 receptor modulation of 5-HT neuron firing in vivo. ACS Chem Neurosci 6:1241–1247

    Article  CAS  PubMed  Google Scholar 

  • Choi HC, Kim YI, Song HK, Kim JE, Kim DS, Kang TC (2010) Effects of selective serotonin reuptake inhibitors on GABAergic inhibition in the hippocampus of normal and pilocarpine induced epileptic rats. Brain Res 1357:131–141

    Article  CAS  PubMed  Google Scholar 

  • Codony X, Vela JM, Ramirez MJ (2011) 5-HT(6) receptor and cognition. Curr Opin Pharmacol 11:94–100

    Article  CAS  PubMed  Google Scholar 

  • Curia G, Longo D, Biagini G, Jones RS, Avoli M (2008) The pilocarpine model of temporal lobe epilepsy. J Neurosci Methods 172:143–157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fu X, Ke M, Yu M, Wang X, Xiao Q, Gu M, Lu Y (2018) Periodic variation of AAK1 in an A-beta1-42 induced mouse model of Alzheimer’s disease. J Mol Neurosci 65:179–189

    Article  CAS  PubMed  Google Scholar 

  • Hermann BP, Seidenberg M, Dow C, Jones J, Rutecki P, Bhattacharya A, Bell B (2006) Cognitive prognosis in chronic temporal lobe epilepsy. Ann Neurol 60:80–87

    Article  PubMed  Google Scholar 

  • Higgs S, Cooper AJ, Barnes NM (2016) The 5-HT2C receptor agonist, lorcaserin, and the 5-HT6 receptor antagonist, SB-742457, promote satiety: a microstructural analysis of feeding behaviour. Psychopharmacology 233:417–424

    Article  CAS  PubMed  Google Scholar 

  • Hu L, Wang B, Zhang Y (2017) Serotonin 5-HT6 receptors affect cognition in a mouse of Alzheimer’s disease by regulating cilia function. Alzheimers Res Ther 9:76

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang H, Che C, Liu C, Jiang F, Mao X (2011) Factors associated with generic and disease-specific quality of life in epilepsy. Biomed Environ Sci 24:228–233

    PubMed  Google Scholar 

  • Huang C, Chi XS, Li R, Hu X, Xu HX, Li JM, Zhou D (2017) Inhibition of P2X7 receptor ameliorates nuclear factor-kappa B mediated neuroinflammation induced by status epilepticus in rat hippocampus. J Mol Neurosci 63:173–184

    Article  CAS  PubMed  Google Scholar 

  • Hughes RN (2004) The value of spontaneous alternation behavior (SAB) as a test of retention in pharmacological investigations of memory. Neurosci Biobehav Rev 28:497–505

    Article  CAS  PubMed  Google Scholar 

  • Inostroza M, Cid E, Brotons-Mas J, Gal B, Aivar P, Uzcategui YG, Sandi C, Menendez de la Prida L (2011) Hippocampal-dependent spatial memory in the water maze is preserved in an experimental model of temporal lobe epilepsy in rats. PLoS One 6:e22372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johnson CN, Ahmed M, Miller ND (2008) 5-HT6 receptor antagonists: prospects for the treatment of cognitive disorders including dementia. Curr Opin Drug Discov Devel 11:642–654

    CAS  PubMed  Google Scholar 

  • Kenyon K, Mintzer S, Nei M (2014) Carbamazepine treatment of generalized tonic-clonic seizure in idiopathic generalized epilepsy. Seizure 23:234–236

    Article  PubMed  Google Scholar 

  • de Lima C, Arida RM, Andersen ML, Polesel DN, de Alvarenga TAF, Vancini RL, Matos G, Tufik S (2017) Effects of acute physical exercise in the light phase of sleep in rats with temporal lobe epilepsy. Epilepsy Res 136:54–61

    Article  PubMed  Google Scholar 

  • Lin WH, Huang HP, Lin MX, Chen SG, Lv XC, Che CH, Lin JL (2013) Seizure-induced 5-HT release and chronic impairment of serotonergic function in rats. Neurosci Lett 534:1–6

    Article  CAS  PubMed  Google Scholar 

  • Marcos B, Gil-Bea FJ, Hirst WD, Garcia-Alloza M, Ramirez MJ (2006) Lack of localization of 5-HT6 receptors on cholinergic neurons: implication of multiple neurotransmitter systems in 5HT6 receptor-mediated acetylcholine release. Eur J Neurosci 24:1299–1306

    Article  PubMed  Google Scholar 

  • Marcos B, Cabero M, Solas M, Aisa B, Ramirez MJ (2010) Signalling pathways associated with 5-HT6 receptors: relevance for cognitive effects. Neuropsychopharmacol 13:775–784

    Article  CAS  Google Scholar 

  • Mitchell ES, Sexton T, Neumaier JF (2007) Increased expression of 5-HT6 receptors in the rat dorsomedial striatum impairs instrumental learning. Neuropsychopharmacology 32:1520–1530

    Article  CAS  PubMed  Google Scholar 

  • Pan Y, Yang H, Claret FX (2014) Emerging roles of Jab1/CSN5 in DNA damage response, DNA repair, and cancer. Cancer Biol Ther 15:256–262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Racine RJ (1972) Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol 32:281–294

    Article  CAS  PubMed  Google Scholar 

  • Rousselet GA, Foxe JJ, Bolam JP (2016) A few simple steps to improve the description of group results in neuroscience. Eur J Neurosci 44:2647–2651

    Article  PubMed  Google Scholar 

  • Routledge C, Bromidge SM, Moss SF, Price GW, Hirst W, Newman H, Riley G, Gager T, Stean T, Upton N, Clarke SE, Brown AM, Middlemiss DN (2000) Characterization of SB-271046: a potent, selective and orally active 5-HT(6) receptor antagonist. Br J Pharmacol 130:1606–1612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Salman MM, Sheilabi MA, Bhattacharyya D, Kitchen P, Conner AC, Bill RM, Woodroofe MN, Conner MT, Princivalle AP (2017) Transcriptome analysis suggests a role for the differential expression of cerebral aquaporins and the MAPK signaling pathway in human temporal lobe epilepsy. Eur J Neurosci 46:2121–2132

    Article  PubMed  Google Scholar 

  • Smith MD, Adams AC, Saunders GW, White HS, Wilcox KS (2007) Phenytoin- and carbamazepine-resistant spontaneous bursting in rat entorhinal cortex is blocked by retigabine in vitro. Epilepsy Res 74:97–106

    Article  CAS  PubMed  Google Scholar 

  • Tai XY, Bernhardt B, Thom M, Thompson P, Baxendale S, Koepp M, Bernasconi N (2018) Review: neurodegenerative processes in temporal lobe epilepsy with hippocampal sclerosis: clinical, pathological and neuroimaging evidence. Neuropathol Appl Neurobiol 44:70–90

    Article  CAS  PubMed  Google Scholar 

  • Titiz AS, Mahoney JM, Testorf ME, Holmes GL, Scott RC (2014) Cognitive impairment in temporal lobe epilepsy: role of online and offline processing of single cell information. Hippocampus 24:1129–1145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Upton N, Blackburn TP, Campbell CA, Cooper D, Evans ML, Herdon HJ, King PD, Ray AM, Stean TO, Chan WN, Evans JM, Thompson M (1997) Profile of SB-204269, a mechanistically novel anticonvulsant drug, in rat models of focal and generalized epileptic seizures. Br J Parmacol 121:1679–1686

    Article  CAS  Google Scholar 

  • Veliskova J (2006) Behavioral characterization of seizures in rats. Elsevier Academic Press, Burlington, pp 601–611

    Google Scholar 

  • Wang L, Lv Y, Deng W, Peng X, Xiao Z, Xi Z, Chen G, Wang X (2015) 5-HT6 receptor recruitment of mTOR modulates seizure activity in epilepsy. Mol Neurobiol 51:1292–1299

    Article  CAS  PubMed  Google Scholar 

  • Wang L, Fu X, Peng X, Xiao Z, Li Z, Chen G, Wang X (2016) DNA methylation profiling reveals correlation of differential methylation patterns with gene expression in human epilepsy. J Mol Neurosci 59:68–77

    Article  CAS  PubMed  Google Scholar 

  • West PJ, Marcy VR, Marino MJ, Schaffhauser H (2009) Activation of the 5-HT(6) receptor attenuates long-term potentiation and facilitates GABAergic neurotransmission in rat hippocampus. Neuroscience 164:692–701

    Article  CAS  PubMed  Google Scholar 

  • Winston GP, Stretton J, Sidhu MK, Symms MR, Thompson PJ, Duncan JS (2013) Structural correlates of impaired working memory in hippocampal sclerosis. Epilepsia 54:1143–1153

    Article  PubMed  PubMed Central  Google Scholar 

  • Woolley ML, Marsden CA, Fone KC (2004) 5-ht6 receptors. Current drug targets. CNS Neurol Dis 3:59–79

    CAS  Google Scholar 

  • Wu Q, Zhao CW, Long Z, Xiao B, Feng L (2018) Anatomy based networks and topology alteration in seizure-related cognitive outcomes. Front Neuroanat 12:25

    Article  PubMed  PubMed Central  Google Scholar 

  • Yang Z, Zhang Y, Wang L (2013) A feedback inhibition between miRNA-127 and TGF-beta/c-Jun cascade in HCC cell migration via MMP12. PLoS One 8:e65256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yun HM, Baik JH, Kang I, Jin C, Rhim H (2010) Physical interaction of Jab1 with human serotonin 6 G-protein-coupled receptor and their possible roles in cell survival. J Biol Chem 285:10016–10029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Dr. Chen Xiao-Chun and his students for their assistance with this research.

Funding

This study was supported by the General Project of National Natural Science Foundation of China (Grant Nos. 81371426 and 81671295).

Author information

Author notes

  1. Changyun Liu and Yuxing Wen contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Fujian Medical University Union Hospital, Xinquan Road 29#, Fuzhou, 350001, China

    Changyun Liu, Huapin Huang, Wanhui Lin, Mingzhu Huang, Rong Lin & Ying Ma

  2. Department of Neurosurgery, Fujian Provincial Hospital, Fuzhou, China

    Yuxing Wen

  3. Fujian Key Laboratory of Molecular Neurology, Fuzhou, China

    Huapin Huang & Wanhui Lin

  4. Department of Geriatrics, Fujian Medical University Union Hospital, Fuzhou, China

    Wanhui Lin

Authors
  1. Changyun Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuxing Wen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Huapin Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wanhui Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mingzhu Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rong Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ying Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Huapin Huang or Wanhui Lin.

Ethics declarations

All procedures were approved by the Local Ethics Committee at the Fujian Medical University Union Hospital.

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

Liu, C., Wen, Y., Huang, H. et al. Over-expression of 5-HT6 Receptor and Activated Jab-1/p-c-Jun Play Important Roles in Pilocarpine-Induced Seizures and Learning-Memory Impairment. J Mol Neurosci 67, 388–399 (2019). https://doi.org/10.1007/s12031-018-1238-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-018-1238-4

Keywords

Search

Navigation