Abstract
Epilepsy is tightly associated with dysfunction of inhibitory GABA neurotransmission. In this study, Krushinsky–Molodkina (KM) rats genetically prone to audiogenic seizures (AGS) were used. KM rats are characterized by the development of audiogenic epilepsy during postnatal ontogenesis, with AGS onset at the age of 1.5–2 months and fully developed AGS expression by 3rd month. We analyzed GABAergic system of the inferior colliculi (IC) of KM rats at different stages of postnatal development. Wistar rats were used as a control. In the IC of young KM rats, Na+/K+/Cl– cotransporter 1 (NKCC1) expression was increased, while K+/Cl– cotransporter 2 (KCC2) was unchanged indicating impairment of postsynaptic GABA action at early stages of postnatal development. Moreover, we revealed also an increase in the expression of vesicular GABA transporter (VGAT) in the IC which additionally pointed on the higher activity of GABA release. In adult rats, in opposite, we revealed a decrease in the expression of KCC2 transporter indicating downregulation of GABA inhibition on the target cells. Thus, GABA dysregulation in the IC can mediate the seizure susceptibility in adult KM rats.
Abbreviations
- KM:
-
Krushinsky–Molodkina rats
- IC:
-
inferior colliculi
- AGS:
-
audiogenic seizure
- KCC2:
-
K+/Cl– cotransporter 2
- NKCC1:
-
Na+/K+/Cl– cotransporter
- VGAT:
-
vesicular GABA transporter
- GABAAR(α):
-
GABA-A receptor α1-subunit
References
Blauwblomme T, Dossi E, Pellegrino C, Goubert E, Iglesias BG, Sainte-Rose C, Rouach N, Nabbout R, Huberfeld G (2019) Gamma-aminobutyric acidergic transmission underlies interictal epileptogenicity in pediatric focal cortical dysplasia. Ann Neurol 85: 204–217. http://www.ncbi.nlm.nih.gov/pubmed/30597612
Wang Y, Wang Y, Chen Z (2018) Double-edged GABAergic synaptic transmission in seizures: The importance of chloride plasticity. Brain Res 1701: 126–136. http://www.ncbi.nlm.nih.gov/pubmed/30201259
Houser CR (2014) Do structural changes in GABA neurons give rise to the epileptic state? Adv Exp Med Biol 813: 151–160. http://www.ncbi.nlm.nih.gov/pubmed/25012374
Goodkin HP, Yeh JL, Kapur J (2005) Status epilepticus increases the intracellular accumulation of GABAA receptors. J Neurosci 25: 5511–5520. http://www.ncbi.nlm.nih.gov/pubmed/15944379
Scharfman HE, Brooks-Kayal AR (2014) Is plasticity of GABAergic mechanisms relevant to epileptogenesis? Adv Exp Med Biol 813: 133–150. http://www.ncbi.nlm.nih.gov/pubmed/25012373
Liu R, Wang J, Liang S, Zhang G, Yang X (2019) Role of NKCC1 and KCC2 in Epilepsy: From Expression to Function. Front Neurol 10: 1407. http://www.ncbi.nlm.nih.gov/pubmed/32010056
Palma E, Amici M, Sobrero F, Spinelli G, Di Angelantonio S, Ragozzino D, Mascia A, Scoppetta C, Esposito V, Miledi R, Eusebi F (2006) Anomalous levels of Cl- transporters in the hippocampal subiculum from temporal lobe epilepsy patients make GABA excitatory. Proc Natl Acad Sci USA 103: 8465–8468. http://www.ncbi.nlm.nih.gov/pubmed/16709666
Vinogradova LV (2017) Audiogenic kindling and secondary subcortico-cortical epileptogenesis: Behavioral correlates and electrographic features. Epilepsy Behav 71: 142–153. http://www.ncbi.nlm.nih.gov/pubmed/26148984
Faingold CL (1999) Neuronal networks in the genetically epilepsy-prone rat. Adv Neurol 79: 311–321. http://www.ncbi.nlm.nih.gov/pubmed/10514823
Ribak CE (2017) An abnormal GABAergic system in the inferior colliculus provides a basis for audiogenic seizures in genetically epilepsy-prone rats. Epilepsy Behav 71: 160–164. http://www.ncbi.nlm.nih.gov/pubmed/25812940
Ribak CE, Morin CL (1995) The role of the inferior colliculus in a genetic model of audiogenic seizures. Anat Embryol (Berl) 191: 279–295. http://www.ncbi.nlm.nih.gov/pubmed/7645755
Lasley SM (1991) Roles of neurotransmitter amino acids in seizure severity and experience in the genetically epilepsy-prone rat. Brain Res 560: 63–70. http://www.ncbi.nlm.nih.gov/pubmed/1684733
Simler S, Ciesielski L, Clement J, Rastegar A, Mandel P (1992) Involvement of synaptosomal neurotransmitter amino acids in audiogenic seizure-susceptibility and -severity of Rb mice. Neurochem Res 17: 953–959. http://www.ncbi.nlm.nih.gov/pubmed/1357566
Fuentes-Santamaria V, Alvarado JC, Herranz AS, Garcia-Atares N, Lopez DE (2008) Decreased levels of GABA in the inferior colliculus of the epilepsy-prone hamster (GPG/Vall). Epilepsy Res 79: 224–227. http://www.ncbi.nlm.nih.gov/pubmed/18372163
Prieto-Martin AI, Aroca-Aguilar JD, Sanchez-Sanchez F, Munoz LJ, Lopez DE, Escribano J, de Cabo C (2017) Molecular and neurochemical substrates of the audiogenic seizure strains: The GASH:Sal model. Epilepsy Behav 71: 218–225. http://www.ncbi.nlm.nih.gov/pubmed/26071997
Lohmann C, Friauf E (1996) Distribution of the calcium-binding proteins parvalbumin and calretinin in the auditory brainstem of adult and developing rats. J Comp Neurol 367: 90–109. http://www.ncbi.nlm.nih.gov/pubmed/8867285
Achilles K, Okabe A, Ikeda M, Shimizu-Okabe C, Yamada J, Fukuda A, Luhmann HJ, Kilb W (2007) Kinetic properties of Cl uptake mediated by Na+-dependent K+-2Cl cotransport in immature rat neocortical neurons. J Neurosci 27: 8616–8627. http://www.ncbi.nlm.nih.gov/pubmed/17687039
Valeeva G, Valiullina F, Khazipov R (2013) Excitatory actions of GABA in the intact neonatal rodent hippocampus in vitro. Front Cell Neurosci 7: 20. http://www.ncbi.nlm.nih.gov/pubmed/23467988
Fedotova IB, Semiokhina AF (2002) Developmental changes in audiogenic epilepsy and myoclonus in KM rats. Zh Vyssh Nerv Deiat Im IP Pavlova 52: 261–265. http://www.ncbi.nlm.nih.gov/pubmed/12013664
Chernigovskaya EV, Dorofeeva NA, Nasluzova EV, Kulikov AA, Ovsyannikova VV, Glazova MV (2018) Apoptosis and proliferation in the inferior colliculus during postnatal development and epileptogenesis in audiogenic Krushinsky-Molodkina rats. Epilepsy Behav 88: 227–234. http://www.ncbi.nlm.nih.gov/pubmed/30316149
Chernigovskaya EV, Dorofeeva NA, Lebedenko OO, Nikolaeva SD, Naumova AA, Lavrova EA, Glazova MV (2019) Neurochemical Organization of the Inferior Colliculus in Audiogenic Krushinsky-Molodkina Rats During Development of Seizure Susceptibility. Russian Journal of Physiology 105: 724–741.
Chaudhry FA, Reimer RJ, Bellocchio EE, Danbolt NC, Osen KK, Edwards RH, Storm-Mathisen J (1998) The vesicular GABA transporter, VGAT, localizes to synaptic vesicles in sets of glycinergic as well as GABAergic neurons. J Neurosci 18: 9733–9750. http://www.ncbi.nlm.nih.gov/pubmed/9822734
Olsen RW, Sieghart W (2009) GABA A receptors: subtypes provide diversity of function and pharmacology. Neuropharmacology 56: 141–148. http://www.ncbi.nlm.nih.gov/pubmed/18760291
Geal-Dor M, Freeman S, Li G, Sohmer H (1993) Development of hearing in neonatal rats: air and bone conducted ABR thresholds. Hear Res 69: 236–242. http://www.ncbi.nlm.nih.gov/pubmed/8226345
Leidenheimer NJ (2008) Regulation of excitation by GABA(A) receptor internalization. Results Probl Cell Differ 44: 1–28. http://www.ncbi.nlm.nih.gov/pubmed/17549438
Barnes EM Jr (1996) Use-dependent regulation of GABAA receptors. Int Rev Neurobiol 39: 53–76. http://www.ncbi.nlm.nih.gov/pubmed/8894844
Blaesse P, Guillemin I, Schindler J, Schweizer M, Delpire E, Khiroug L, Friauf E, Nothwang HG (2006) Oligomerization of KCC2 correlates with development of inhibitory neurotransmission. J Neurosci 26: 10407–10419. http://www.ncbi.nlm.nih.gov/pubmed/17035525
Lu J, Karadsheh M, Delpire E (1999) Developmental regulation of the neuronal-specific isoform of K-Cl cotransporter KCC2 in postnatal rat brains. J Neurobiol 39: 558–568. http://www.ncbi.nlm.nih.gov/pubmed/10380077
Kanaka C, Ohno K, Okabe A, Kuriyama K, Itoh T, Fukuda A, Sato K (2001) The differential expression patterns of messenger RNAs encoding K-Cl cotransporters (KCC1,2) and Na-K-2Cl cotransporter (NKCC1) in the rat nervous system. Neuroscience 104: 933–946. http://www.ncbi.nlm.nih.gov/pubmed/11457581
Wang C, Shimizu-Okabe C, Watanabe K, Okabe A, Matsuzaki H, Ogawa T, Mori N, Fukuda A, Sato K (2002) Developmental changes in KCC1, KCC2, and NKCC1 mRNA expressions in the rat brain. Brain Res Dev Brain Res 139: 59–66. http://www.ncbi.nlm.nih.gov/pubmed/12414094
Solius GM, Poletaeva II, Revishchin AV (2016) Audiogenic epilepsy and GABAergic system of the colliculus inferior in Krushinsry-Molodkina rats. Dokl Biochem Biophys 466: 32–34.
Acknowledgments
Part of the analysis was done at Research Resource Center no. 441590 at Sechenov Institute of Evolutionary Physiology and Biochemistry, the Russian Academy of Sciences.
Funding
This study was supported by the Russian Government Program no. 075-967-23-00.
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Conceptualization, S.D.N., E.V.C.; methodology, A.A.N., E.V.C.; formal analysis, A.A.N., A.P.I.,; investigation, A.P.I., S.D.N., A.A.N.; data curation, E.V.C.; writing—original draft preparation, A.P.I., E.V.C.; writing—review and editing, A.A.N., M.V.G.; visualization, A.P.I., S.D.N., A.A.K.; supervision, M.V.G.; funding acquisition, E.V.C. All authors have read and agreed to the published version of the manuscript.
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All experiments with rats were conducted in accordance with EC Directive 86/609/EEC for animal experiments and approved by the Institutional Animal Care and Use Committee at the Sechenov Institute of Evolutionary Physiology and Biochemistry (protocol code 6-3/2022, June 23, 2022).
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The authors declare no conflict of interest.
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Translated by A. Polyanovsky
Russian Text © The Author(s), 2023, published in Rossiiskii Fiziologicheskii Zhurnal imeni I.M. Sechenova, 2023, Vol. 109, No. 7, pp. 890–901https://doi.org/10.31857/S0869813923070105.
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Nikolaeva, S.D., Ivlev, A.P., Naumova, A.A. et al. Dysregulation of GABAergic System in the Inferior Colliculi of Rats during the Development of Audiogenic Epilepsy. J Evol Biochem Phys 59, 1252–1261 (2023). https://doi.org/10.1134/S002209302304018X
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DOI: https://doi.org/10.1134/S002209302304018X