Abstract
The synchronization of astrocytes via gap junctions (GJ) is a crucial mechanism in epileptic conditions, contributing to the synchronization of the neuronal networks. Little is known about the endogenous response of GJ in genetic absence epileptic animal models. We evaluated and quantified astrocyte GJ protein connexin (Cx) 30 and 43 in the somatosensory cortex (SSCx), ventrobasal (VB), centromedian (CM), lateral geniculate (LGN) and thalamic reticular (TRN) nuclei of thalamus of genetic absence epilepsy rats from Strasbourg (GAERS), Wistar albino glaxo rats from Rijswijk (WAG/Rij) and control Wistar animals using immunohistochemistry and Western Blot. The Cx30 and Cx43 immunopositive astrocytes per unit area were quantified for each region of the three animal strains. Furthermore, Cx30 and Cx43 Western Blot was applied to the tissue samples from the same regions of the three strain. The number of Cx30 immunopositive astrocytes showed significant increase in both GAERS and WAG/Rij compared to control Wistar in all brain regions studied except LGN of WAG/Rij animals. Furthermore, Cx43 in both GAERS and WAG/Rij showed significant increase in SSCx, VB and TRN. The protein expression was increased in both Cx30 and Cx43 in the two epileptic strains compared to control Wistar animals. The significant increase in the astrocytic GJ proteins Cx30 and Cx43 and the differences in the co-expression of Cx30 and Cx43 in the genetically absence epileptic strains compared to control Wistar animals may suggest that astrocytic Cx’s may be involved in the mechanism of absence epilepsy. Increased number of astrocytic Cx’s in GAERS and WAG/Rij may represent a compensatory response of the thalamocortical circuitry to the absence seizures or may be related to the production and/or development of absence seizures.
Similar content being viewed by others
Change history
11 January 2022
A Correction to this paper has been published: https://doi.org/10.1007/s00429-022-02452-7
07 April 2023
This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1007/s00429-023-02640-z
References
Araque A, Carmignoto G, Haydon PG et al (2014) Gliotransmitters travel in time and space. Neuron 81:728–739. https://doi.org/10.1016/j.neuron.2014.02.007
Barres BA (2008) The mystery and magic of glia: a perspective on their roles in health and disease. Neuron 60:430–440. https://doi.org/10.1016/j.neuron.2008.10.013
Birioukova LM, Midzyanovskaya IS, Lensu S et al (2005) Distribution of D1-like and D2-like dopamine receptors in the brain of genetic epileptic WAG/Rij rats. Epilepsy Res 63:89–96. https://doi.org/10.1016/j.eplepsyres.2004.12.001
Carmichael ST (2006) Cellular and molecular mechanisms of neural repair after stroke: making waves. Ann Neurol 59:735–742. https://doi.org/10.1002/ana.20845
Çavdar S, Kuvvet Y, Sur-Erdem I et al (2019) Relationships between astrocytes and absence epilepsy in rat: an experimental study. Neurosci Lett 712:134518. https://doi.org/10.1016/j.neulet.2019.134518
Coenen AML, Van Luijtelaar ELJM (2003) Genetic animal models for absence epilepsy: a review of the WAG/Rij strain of rats. Behav Genet 33:635–655. https://doi.org/10.1023/a:1026179013847
Cope DW, Di Giovanni G, Fyson SJ et al (2009) Enhanced tonic GABAA inhibition in typical absence epilepsy. Nat Med 15:1392–1398. https://doi.org/10.1038/nm.2058
Dallérac G, Rouach N (2016) Astrocytes as new targets to improve cognitive functions. Prog Neurobiol 144:48–67. https://doi.org/10.1016/j.pneurobio.2016.01.003
Danober L, Deransart C, Depaulis A et al (1998) Pathophysiological mechanisms of genetic absence epilepsy in the rat. Prog Neurobiol 55:27–57. https://doi.org/10.1016/s0301-0082(97)00091-9
De Keyser J, Mostert JP, Koch MW (2008) Dysfunctional astrocytes as key players in the pathogenesis of central nervous system disorders. J Neurol Sci 267:3–16. https://doi.org/10.1016/j.jns.2007.08.044
Fellin T, Carmignoto G (2004) Neurone-to-astrocyte signalling in the brain represents a distinct multifunctional unit. J Physiol 559:3–15. https://doi.org/10.1113/jphysiol.2004.063214
Fonseca CG, Green CR, Nicholson LFB (2002) Upregulation in astrocytic connexin 43 gap junction levels may exacerbate generalized seizures in mesial temporal lobe epilepsy. Brain Res 929:105–116. https://doi.org/10.1016/s0006-8993(01)03289-9
Furnari FB, Fenton T, Bachoo RM et al (2007) Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev 21:2683–2710. https://doi.org/10.1101/gad.1596707
Gareri P, Condorelli D, Belluardo N et al (2005) Antiabsence effects of carbenoxolone in two genetic animal models of absence epilepsy (WAG/Rij rats and lh/lh mice). Neuropharmacology 49:551–563. https://doi.org/10.1016/j.neuropharm.2005.04.012
Gil JM, Rego AC (2008) Mechanisms of neurodegeneration in Huntington’s disease. Eur J Neurosci 27:2803–2820. https://doi.org/10.1111/j.1460-9568.2008.06310.x
Halassa MM, Fellin T, Haydon PG (2007) The tripartite synapse: roles for gliotransmission in health and disease. Trends Mol Med 13:54–63. https://doi.org/10.1016/j.molmed.2006.12.005
Halassa MM, Fellin T, Haydon PG (2009) Tripartite synapses: roles for astrocytic purines in the control of synaptic physiology and behavior. Neuropharmacology 57:343–346. https://doi.org/10.1016/j.neuropharm.2009.06.031
Han J-K, Kwon S-H, Kim YG et al (2021) Ablation of STAT3 in Purkinje cells reorganizes cerebellar synaptic plasticity in long-term fear memory network. Elife 10:e63291
Kuhlmann T, Lassmann H, Brück W (2008) Diagnosis of inflammatory demyelination in biopsy specimens: a practical approach. Acta Neuropathol 115:275–287. https://doi.org/10.1007/s00401-007-0320-8
Lapato AS, Tiwari-Woodruff SK (2018) Connexins and pannexins: at the junction of neuro-glial homeostasis & disease. J Neurosci Res 96:31–44. https://doi.org/10.1002/jnr.24088
Mahmoud AA, Abdelmagid T, AlGhofely M et al (2020) Epilepsy in patients with insulin-dependent diabetes and relation to glutamic acid decarboxylase 65. Neurosciences (riyadh). https://doi.org/10.17712/nsj.2020.3.20190057
Melø TM, Sonnewald U, Bastholm IA, Nehlig A (2007) Astrocytes may play a role in the etiology of absence epilepsy: a comparison between immature GAERS not yet expressing seizures and adults. Neurobiol Dis 28:227–235. https://doi.org/10.1016/j.nbd.2007.07.011
Nagele RG, Wegiel J, Venkataraman V et al (2004) Contribution of glial cells to the development of amyloid plaques in Alzheimer’s disease. Neurobiol Aging 25:663–674. https://doi.org/10.1016/j.neurobiolaging.2004.01.007
Nagy JI, Rash JE (2000) Connexins and gap junctions of astrocytes and oligodendrocytes in the CNS. Brain Res Brain Res Rev 32:29–44. https://doi.org/10.1016/s0165-0173(99)00066-1
Nagy JI, Patel D, Ochalski PA, Stelmack GL (1999) Connexin30 in rodent, cat and human brain: selective expression in gray matter astrocytes, co-localization with connexin43 at gap junctions and late developmental appearance. Neuroscience 88:447–468. https://doi.org/10.1016/s0306-4522(98)00191-2
Nagy JI, Li X, Rempel J et al (2001) Connexin26 in adult rodent central nervous system: demonstration at astrocytic gap junctions and colocalization with connexin30 and connexin43. J Comp Neurol 441:302–323
Nagy JI, Dudek FE, Rash JE (2004) Update on connexins and gap junctions in neurons and glia in the mammalian nervous system. Brain Res Brain Res Rev 47:191–215. https://doi.org/10.1016/j.brainresrev.2004.05.005
Nedergaard M, Ransom B, Goldman SA (2003) New roles for astrocytes: redefining the functional architecture of the brain. Trends Neurosci 26:523–530. https://doi.org/10.1016/j.tins.2003.08.008
Nersesyan H, Hyder F, Rothman DL, Blumenfeld H (2004) Dynamic fMRI and EEG recordings during spike-wave seizures and generalized tonic-clonic seizures in WAG/Rij rats. J Cereb Blood Flow Metab 24:589–599. https://doi.org/10.1097/01.WCB.0000117688.98763.23
Nishie M, Mori F, Ogawa M et al (2004) Multinucleated astrocytes in old demyelinated plaques in a patient with multiple sclerosis. Neuropathology 24:248–253. https://doi.org/10.1111/j.1440-1789.2004.00548.x
Panayiotopoulos CP (2001) Treatment of typical absence seizures and related epileptic syndromes. Paediatr Drugs 3:379–403. https://doi.org/10.2165/00128072-200103050-00006
Pannasch U, Vargová L, Reingruber J et al (2011) Astroglial networks scale synaptic activity and plasticity. Proc Natl Acad Sci USA 108:8467–8472. https://doi.org/10.1073/pnas.1016650108
Paxinos G, Watson C (2013) The rat brain in stereotaxic coordinates. Elsevier Science
Rothstein JD, Martin LJ, Kuncl RW (1992) Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. N Engl J Med 326:1464–1468. https://doi.org/10.1056/NEJM199205283262204
Seifert G, Schilling K, Steinhäuser C (2006) Astrocyte dysfunction in neurological disorders: a molecular perspective. Nat Rev Neurosci 7:194–206. https://doi.org/10.1038/nrn1870
Sofroniew MV (2009) Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci 32:638–647. https://doi.org/10.1016/j.tins.2009.08.002
Steinhäuser C, Seifert G, Bedner P (2012) Astrocyte dysfunction in temporal lobe epilepsy: K+ channels and gap junction coupling. Glia 60:1192–1202. https://doi.org/10.1002/glia.22313
Swayne LA, Bennett SAL (2016) Connexins and pannexins in neuronal development and adult neurogenesis. BMC Cell Biol 17(Suppl 1):10. https://doi.org/10.1186/s12860-016-0089-5
Tenney JR, Glauser TA (2013) The current state of absence epilepsy: can we have your attention? Epilepsy Curr 13:135–140. https://doi.org/10.5698/1535-7511-13.3.135
Vicario N, Zappalà A, Calabrese G et al (2017) Connexins in the central nervous system: physiological traits and neuroprotective targets. Front Physiol 8:1060. https://doi.org/10.3389/fphys.2017.01060
Vincze R, Péter M, Szabó Z et al (2019) Connexin 43 differentially regulates epileptiform activity in models of convulsive and non-convulsive epilepsies. Front Cell Neurosci 13:173. https://doi.org/10.3389/fncel.2019.00173
Wan CK, Shaikh SB, Green CR, Nicholson LFB (2012) Comparison of bidirectional and bicistronic inducible systems for coexpression of connexin genes and fluorescent reporters. Anal Biochem 431:90–95
White TW, Bruzzone R (1996) Multiple connexin proteins in single intercellular channels: connexin compatibility and functional consequences. J Bioenerg Biomembr 28:339–350
Yamamura S, Hoshikawa M, Dai K et al (2013) ONO-2506 inhibits spike-wave discharges in a genetic animal model without affecting traditional convulsive tests via gliotransmission regulation. Br J Pharmacol 168:1088–1100. https://doi.org/10.1111/j.1476-5381.2012.02132.x
Acknowledgements
The authors would like to thank Koç University Research Center for Translational Medicine (KUTTAM) for using the facilities.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. All authors declare that they have no actual or potential conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This article has been retracted. Please see the retraction notice for more detail:https://doi.org/10.1007/s00429-023-02640-z
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.
About this article
Cite this article
Çavdar, S., Köse, B., Sur-Erdem, İ. et al. RETRACTED ARTICLE: Comparing astrocytic gap junction of genetic absence epileptic rats with control rats: an experimental study. Brain Struct Funct 226, 2113–2123 (2021). https://doi.org/10.1007/s00429-021-02310-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00429-021-02310-y