Russian Journal of PhysiologyRussian Journal of PhysiologyРоссийский физиологический журнал им. И.М. Сеченова0869-81392658-655XThe Russian Academy of Sciences65154610.31857/S0869813923070105XMXKRZEXPERIMENTAL ARTICLESЭКСПЕРИМЕНТАЛЬНЫЕ СТАТЬИDysregulation of GABAergic System in the Inferior Colliculi of Rats during the Development of Audiogenic EpilepsyНарушение регуляции ГАМК-ергической системы в нижних буграх четверохолмия крыс при развитии аудиогенной эпилепсииNikolaevaS. D.НиколаеваС. Д.mglazova@iephb.ruIvlevA. P.ИвлевА. П.mglazova@iephb.ruNaumovaA. A.НаумоваА. А.mglazova@iephb.ruKulikovA. A.КуликовА. А.mglazova@iephb.ruGlazovaM. V.ГлазоваМ. В.mglazova@iephb.ruChernigovskayaE. V.ЧерниговскаяЕ. В.mglazova@iephb.ruSechenov Institute of Evolutionary Physiology and Biochemistry, the Russian Academy of SciencesИнститут эволюционной физиологии и биохимии им. И.М. Сеченова Российской академии наук01072023109789090101022025Copyright ©; 2023, С.Д. Николаева, А.П. Ивлев, А.А. Наумова, А.А. Куликов, М.В. Глазова, Е.В. ЧерниговскаяCopyright ©; 2023, С.Д. Николаева, А.П. Ивлев, А.А. Наумова, А.А. Куликов, М.В. Глазова, Е.В. Черниговская2023С.Д. Николаева, А.П. Ивлев, А.А. Наумова, А.А. Куликов, М.В. Глазова, Е.В. ЧерниговскаяС.Д. Николаева, А.П. Ивлев, А.А. Наумова, А.А. Куликов, М.В. Глазова, Е.В. Черниговскаяhttps://journals.eco-vector.com/0869-8139/article/view/651546

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.

Эпилепсия тесно связана с нарушением функции тормозной ГАМК-нейротрансмиссии. В данном исследовании использовались крысы Крушинского–Молодкиной (КМ), генетически склонные к аудиогенным припадкам (АГП). Для крыс КМ характерно развитие аудиогенной эпилепсии в постнатальном онтогенезе, с началом АГП в возрасте 1.5–2 мес. и полным развитием экспрессии АГП к 3 месяцам. Мы проанализировали ГАМК-ергическую систему нижних бугров четверохолмия (НБЧ) крыс КМ на разных стадиях постнатального развития. В качестве контроля использовали крыс линии Вистар. В НБЧ молодых крыс линии КМ экспрессия Na+/K+/Cl– котранспортера 1 (NKCC1) была увеличена, в то время как K+/Cl– котранспортер 2 (KCC2) был неизменен, что указывает на нарушение постсинаптического действия ГАМК на ранних стадиях постнатального развития. Более того, мы выявили увеличение экспрессии везикулярного транспортера ГАМК (VGAT) в НБЧ, что дополнительно указывает на более высокую активность высвобождения ГАМК. У взрослых крыс, напротив, выявлено снижение экспрессии транспортера KCC2, что указывает на снижение ГАМК-опосредованного торможения в клетках-мишенях. Таким образом, восприимчивость к судорогам у взрослых крыс КМ может быть вызвана нарушениями регуляции ГАМК в НБЧ.

Krushinsky–Molodkina ratsaudiogenic seizuresinferior colliculipostnatal ontogenesisкрысы Крушинского–Молодкинойаудиогенные судорогинижняя колликулапостнатальный онтогенезBlauwblomme 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. https://doi.org/10.1002/ana.25403Wang Y, Wang Y, Chen Z (2018) Double-edged GABAergic synaptic transmission in seizures: The importance of chloride plasticity. Brain Res 1701: 126–136. https://doi.org/10.1016/j.brainres.2018.09.008Houser CR (2014) Do structural changes in GABA neurons give rise to the epileptic state? Adv Exp Med Biol 813: 151–160. https://doi.org/10.1007/978-94-017-8914-1_12Goodkin HP, Yeh JL, Kapur J (2005) Status epilepticus increases the intracellular accumulation of GABAA receptors. J Neurosci 25: 5511–5520. https://doi.org/10.1523/JNEUROSCI.0900-05.2005Scharfman HE, Brooks-Kayal AR (2014) Is plasticity of GABAergic mechanisms relevant to epileptogenesis? Adv Exp Med Biol 813: 133–150. https://doi.org/10.1007/978-94-017-8914-1_11Liu 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. https://doi.org/10.3389/fneur.2019.01407Palma 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 U S A 103: 8465–8468. https://doi.org/10.1073/pnas.0602979103Vinogradova LV (2017) Audiogenic kindling and secondary subcortico-cortical epileptogenesis: Behavioral correlates and electrographic features. Epilepsy Behav 71: 142–153. https://doi.org/10.1016/j.yebeh.2015.06.014Faingold CL (1999) Neuronal networks in the genetically epilepsy-prone rat. Adv Neurol 79: 311–321.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. https://doi.org/10.1016/j.yebeh.2015.02.024Ribak CE, Morin CL (1995) The role of the inferior colliculus in a genetic model of audiogenic seizures. Anat Embryol (Berl) 191: 279–295. https://doi.org/10.1007/BF00534681Lasley SM (1991) Roles of neurotransmitter amino acids in seizure severity and experience in the genetically epilepsy-prone rat. Brain Res 560: 63–70.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. https://doi.org/10.1007/BF00993272Fuentes-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. https://doi.org/10.1016/j.eplepsyres.2008.02.003Prieto-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. https://doi.org/10.1016/j.yebeh.2015.05.025Lohmann 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. https://doi.org/10.1002/(SICI)1096-9861(19960325)367:1<90::AID-CNE7>3.0.CO;2-EAchilles 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. https://doi.org/10.1523/JNEUROSCI.5041-06.2007Valeeva G, Valiullina F, Khazipov R (2013) Excitatory actions of GABA in the intact neonatal rodent hippocampus in vitro. Front Cell Neurosci 7: 20. https://doi.org/10.3389/fncel.2013.00020Федотова ИБ, Семиохина АФ (2002) Аудиогенная эпилепсия и миоклонус в онтогенезе крыс КМ. Журн высш нерв деят 52(2): 261–265. [Fedotova IB, Semiokhina AF (2002) Developmental changes in audiogenic epilepsy and myoclonus in KM rats. Zh Vyssh Nerv Deiat Im I P Pavlova 52(2): 261–265. (In Russ)].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. https://doi.org/10.1016/j.yebeh.2018.09.023Chernigovskaya 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. Russ J Physiol 105: 724–741. https://doi.org/10.1134/S0869813919060013Chaudhry 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. https://doi.org/10.1523/JNEUROSCI.18-23-09733.1998Olsen RW, Sieghart W (2009) GABA A receptors: subtypes provide diversity of function and pharmacology. Neuropharmacology 56: 141–148. https://doi.org/10.1016/j.neuropharm.2008.07.045Geal-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. https://doi.org/10.1016/0378-5955(93)90113-fChernigovskaya EV, Korotkov AA, Dorofeeva NA, Gorbacheva EL, Kulikov AA, Glazova MV (2019) Delayed audiogenic seizure development in a genetic rat model is associated with overactivation of ERK1/2 and disturbances in glutamatergic signaling. Epilepsy Behav 99: 106494. https://doi.org/10.1016/j.yebeh.2019.106494Leidenheimer NJ (2008) Regulation of excitation by GABA(A) receptor internalization. Results Probl Cell Differ 44: 1–28. https://doi.org/10.1007/400_2007_039Barnes EM Jr (1996) Use-dependent regulation of GABAA receptors. Int Rev Neurobiol 39: 53–76. https://doi.org/10.1016/s0074-7742(08)60663-7Blaesse 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. https://doi.org/10.1523/JNEUROSCI.3257-06.2006Lu 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.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. https://doi.org/10.1016/s0306-4522(01)00149-xWang 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. https://doi.org/10.1016/s0165-3806(02)00536-9Solius GM, Revishchin AV, Pavlova GV, Poletaeva II (2016) Audiogenic epilepsy and GABAergic system of the colliculus inferior in Krushinsry-Molodkina rats Dokl Biochem Biophys 466: 32–34.https://doi.org/10.1134/S1607672916010099