ИССЛЕДОВАНИЕ ФУНКЦИОНАЛЬНОГО СТАТУСА АСТРОГЛИИ ГИППОКАМПА У КРЫС С ГЕНЕТИЧЕСКОЙ ПРЕДРАСПОЛОЖЕННОСТЬЮ К АУДИОГЕННЫМ СУДОРОГАМ
PDF

Ключевые слова

астроциты
аудиогенные судороги
гиппокамп
крысы Крушинского-Молодкиной
эпилепсия

Аннотация

Известно, что нарушения функций астроцитов могут приводить к изменению возбудимости нейронов и, как следствие, к развитию эпилепсии, однако данный вопрос требует дальнейшего изучения. Целью настоящей работы являлась оценка функционального состояния астроцитов гиппокампа у крыс линии Крушинского-Молодкиной (КМ) с наследственной предрасположенностью к рефлекторным аудиогенным судорогам. В экспериментах были использованы «наивные» взрослые животные с полностью сформированной судорожной готовностью. В качестве контроля использовали крыс материнской популяции Вистар. Полученные результаты не выявили различий в экспрессии астроцитарных белков GFAP, ALDH1L1 и NFIA, что свидетельствует об отсутствии в гиппокампе крыс КМ реактивного астроглиоза. Экспрессия SPARC и аквапорина 4 также не отличалась от контрольного уровня, указывая на отсутствие нарушений в астроцитарной регуляции синаптогенеза и водного транспорта. Анализ глиальных белков, отвечающих за обратный захват и метаболизм нейромедиаторов, выявил нормальный уровень экспрессии транспортёра ГАМК GAT-3 и глутаминсинтетазы, однако содержание транспортёров глутамата EAAT1 и 2 было достоверно повышено, что свидетельствует о более активной утилизации синаптического глутамата. Кроме того, сниженная экспрессия гликолитического фермента альдолазы С в гиппокампе крыс КМ, вероятно, указывает на недостаточную активность метаболизма глюкозы. Таким образом, полученные данные выявили генетически детерминированные изменения функционального статуса астроцитов в гиппокампе крыс с наследственной рефлекторной эпилепсией.

PDF

Литература

Verkhratsky A, Nedergaard M (2018) Physiology of astroglia. Physiol Rev 98:239–389. s://doi.org/10.1152/physrev.00042.2016

Pekny M, Pekna M, Messing A, Steinhäuser C, Lee J-M, Parpura V, Hol EM, Sofroniew M V., Verkhratsky A (2016) Astrocytes: a central element in neurological diseases. Acta Neuropathol 131:323–345. s://doi.org/10.1007/s00401-015-1513-1

Kovács R, Heinemann U, Steinhäuser C (2012) Mechanisms underlying blood–brain barrier dysfunction in brain pathology and epileptogenesis: Role of astroglia. Epilepsia 53:53–59. s://doi.org/10.1111/j.1528-1167.2012.03703.x

Halassa MM, Haydon PG (2010) Integrated Brain Circuits: Astrocytic Networks Modulate Neuronal Activity and Behavior. Annu Rev Physiol 72:335–355. s://doi.org/10.1146/annurev-physiol-021909-135843

Perea G, Navarrete M, Araque A (2009) Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci 32:421–431. s://doi.org/10.1016/j.tins.2009.05.001

Seifert G, Schilling K, Steinhäuser C (2006) Astrocyte dysfunction in neurological disorders: a molecular perspective. Nat Rev Neurosci 7:194–206. s://doi.org/10.1038/nrn1870

Jabs R, Seifert G, Steinhäuser C (2008) Astrocytic function and its alteration in the epileptic brain. Epilepsia 49:3–12. s://doi.org/10.1111/j.1528-1167.2008.01488.x

Binder DK, Steinhäuser C (2006) Functional changes in astroglial cells in epilepsy. Glia 54:358–368. s://doi.org/10.1002/glia.20394

Sparks FT, Liao Z, Li W, Grosmark A, Soltesz I, Losonczy A (2020) Hippocampal adult-born granule cells drive network activity in a mouse model of chronic temporal lobe epilepsy. Nat Commun 2020 111 11:1–13. s://doi.org/10.1038/s41467-020-19969-2

Devinsky O, Vezzani A, Najjar S, De Lanerolle NC, Rogawski MA (2013) Glia and epilepsy: excitability and inflammation. Trends Neurosci 36:174–184. s://doi.org/10.1016/j.tins.2012.11.008

Wetherington J, Serrano G, Dingledine R (2008) Astrocytes in the Epileptic Brain. Neuron 58:168–178. s://doi.org/10.1016/j.neuron.2008.04.002

Clarke LE, Liddelow SA, Chakraborty C, Münch AE, Heiman M, Barres BA (2018) Normal aging induces A1-like astrocyte reactivity. Proc Natl Acad Sci 115:E1896–E1905. s://doi.org/10.1073/PNAS.1800165115

Heuser K, Eid T, Lauritzen F, Thoren AE, Vindedal GF, Taubøll E, Gjerstad L, Spencer DD, Ottersen OP, Nagelhus EA, De Lanerolle NC (2012) Loss of perivascular kir4.1 potassium channels in the sclerotic hippocampus of patients with mesial temporal lobe epilepsy. J Neuropathol Exp Neurol 71:814–825. s://doi.org/10.1097/NEN.0b013e318267b5af

Sandhu MRS, Gruenbaum BF, Gruenbaum SE, Dhaher R, Deshpande K, Funaro MC, Lee T-SW, Zaveri HP, Eid T (2021) Astroglial Glutamine Synthetase and the Pathogenesis of Mesial Temporal Lobe Epilepsy. Front Neurol 12:665334. s://doi.org/10.3389/fneur.2021.665334

Poletaeva II, Surina NM, Kostina ZA, Perepelkina OV, Fedotova IB (2017) The Krushinsky-Molodkina rat strain: The study of audiogenic epilepsy for 65 years. Epilepsy Behav 71:130–141. s://doi.org/10.1016/j.yebeh.2015.04.072

Kulikov AA, Naumova AA, Aleksandrova EP, Glazova MV, Chernigovskaya EV (2021) Audiogenic kindling stimulates aberrant neurogenesis, synaptopodin expression, and mossy fiber sprouting in the hippocampus of rats genetically prone to audiogenic seizures. Epilepsy Behav 125. s://doi.org/10.1016/j.yebeh.2021.108445

Kulikov AA, Naumova AA, Dorofeeva NA, Ivlev AP, Glazova M V., Chernigovskaya E V (2022) Dynamics of neurodegeneration in the hippocampus of Krushinsky-Molodkina rats correlates with the progression of limbic seizures. Epilepsy Behav 134. s://doi.org/10.1016/j.yebeh.2022.108846

Kulikov AA, Dorofeeva NA, Naumova AA, Harbachova EL, Glazova MV, Chernigovskaya EV (2020) Impaired postnatal development of the hippocampus of Krushinsky-Molodkina rats genetically prone to audiogenic seizures. Epilepsy Behav 113. s://doi.org/10.1016/j.yebeh.2020.107526

Chernigovskaya 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. s://doi.org/10.1016/j.yebeh.2019.106494

Matias I, Morgado J, Gomes FCA (2019) Astrocyte Heterogeneity: Impact to Brain Aging and Disease. Front Aging Neurosci 11:59. s://doi.org/10.3389/fnagi.2019.00059

Laug D, Huang TW, Bosquez Huerta NA, Huang AYS, Sardar D, Ortiz-Guzman J, Carlson JC, Arenkiel BR, Kuo CT, Mohila CA, Glasgow SM, Lee HK, Deneen B (2019) Nuclear factor I-A regulates diverse reactive astrocyte responses after CNS injury. J Clin Invest 129:4408–4418. s://doi.org/10.1172/JCI127492

Kucukdereli H, Allen NJ, Lee AT, Feng A, Ozlu MI, Conatser LM, Chakraborty C, Workman G, Weaver M, Sage EH, Barres BA, Eroglu C (2011) Control of excitatory CNS synaptogenesis by astrocyte-secreted proteins hevin and SPARC. Proc Natl Acad Sci U S A 108:E440–E449. s://doi.org/10.1073/pnas.1104977108

Binder DK, Nagelhus EA, Ottersen OP (2012) Aquaporin‐4 and epilepsy. Glia 60:1203–1214. s://doi.org/10.1002/glia.22317

Michalovicz LT, Kelly KA, Vashishtha S, Ben-Hamo R, Efroni S, Miller J V., Locker AR, Sullivan K, Broderick G, Miller DB, O’Callaghan JP (2019) Astrocyte-specific transcriptome analysis using the ALDH1L1 bacTRAP mouse reveals novel biomarkers of astrogliosis in response to neurotoxicity. J Neurochem 150:420–440. s://doi.org/10.1111/jnc.14800

Beard E, Lengacher S, Dias S, Magistretti PJ, Finsterwald C (2022) Astrocytes as Key Regulators of Brain Energy Metabolism: New Therapeutic Perspectives. Front Physiol 12:2503. s://doi.org/10.3389/fphys.2021.825816

Fei Y, Shi R, Song Z, Wu J (2020) Metabolic Control of Epilepsy: A Promising Therapeutic Target for Epilepsy. Front Neurol 11:592514. s://doi.org/10.3389/fneur.2020.592514

Khatibi VA, Salimi M, Rahdar M, Rezaei M, Nazari M, Dehghan S, Davoudi S, Raoufy MR, Mirnajafi-Zadeh J, Javan M, Hosseinmardi N, Behzadi G, Janahmadi M (2023) Glycolysis inhibition partially resets epilepsy-induced alterations in the dorsal hippocampus-basolateral amygdala circuit involved in anxiety-like behavior. Sci Rep 13:6520. s://doi.org/10.1038/s41598-023-33710-1

Cañete-Soler R, Reddy KS, Tolan DR, Zhai J (2005) Aldolases A and C are ribonucleolytic components of a neuronal complex that regulates the stability of the light-neurofilament mRNA. J Neurosci 25:4353–4364. s://doi.org/10.1523/JNEUROSCI.0885-05.2005

Slemmer JE, Haasdijk ED, Engel DC, Plesnila N, Weber JT (2007) Aldolase C-positive cerebellar Purkinje cells are resistant to delayed death after cerebral trauma and AMPA-mediated excitotoxicity. Eur J Neurosci 26:649–656. s://doi.org/10.1111/j.1460-9568.2007.05708.x

Staugaitis SM, Zerlin M, Hawkes R, Levine JM, Goldman JE (2001) Aldolase C/zebrin II expression in the neonatal rat forebrain reveals cellular heterogeneity within the subventricular zone and early astrocyte differentiation. J Neurosci 21:6195–6205. s://doi.org/10.1523/jneurosci.21-16-06195.2001

Magi S, Piccirillo S, Amoroso S, Lariccia V (2019) Excitatory Amino Acid Transporters (EAATs): Glutamate Transport and Beyond. Int J Mol Sci 20:5674. s://doi.org/10.3390/ijms20225674

Todd AC, Hardingham GE (2020) The Regulation of Astrocytic Glutamate Transporters in Health and Neurodegenerative Diseases. Int J Mol Sci 21:9607. s://doi.org/10.3390/ijms21249607

Tanaka K, Watase K, Manabe T, Yamada K, Watanabe M, Takahashi K, Iwama H, Nishikawa T, Ichihara N, Kikuchi T, Okuyama S, Kawashima N, Hori S, Takimoto M, Wada K (1997) Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science (80) 276:1699–1702. s://doi.org/10.1126/science.276.5319.1699

Mathern GW, Mendoza D, Lozada A, Pretorius JK, Dehnes Y, Danbolt NC, Nelson N, Leite JP, Chimelli L, Born DE, Sakamoto AC, Assirati JA, Fried I, Peacock WJ, Ojemann GA, Adelson PD (1999) Hippocampal GABA and glutamate transporter immunoreactivity in patients with temporal lobe epilepsy. Neurology 52:453–472. s://doi.org/10.1212/wnl.52.3.453

Tessler S, Danbolt NC, Faull RLM, Storm-Mathisen J, Emson PC (1999) Expression of the glutamate transporters in human temporal lobe epilepsy. Neuroscience 88:1083–1091. s://doi.org/10.1016/S0306-4522(98)00301-7

Eid T, Thomas MJ, Spencer DD, Rundén-Pran E, Lai JCK, Malthankar G V., Kim JH, Danbolt NC, Ottersen OP, De Lanerolle NC (2004) Loss of glutamine synthetase in the human epileptogenic hippocampus: Possible mechanism for raised extracellular glutamate in mesial temporal lobe epilepsy. Lancet 363:28–37. s://doi.org/10.1016/S0140-6736(03)15166-5

Proper EA, Hoogland G, Kappen SM, Jansen GH, Rensen MGA, Schrama LH, Van Veelen CWM, Van Rijen PC, Van Nieuwenhuizen O, Gispen WH, De Graan PNE (2002) Distribution of glutamate transporters in the hippocampus of patients with pharmaco-resistant temporal lobe epilepsy. Brain 125:32–43. s://doi.org/10.1093/brain/awf001

Liu J, Feng X, Wang Y, Xia X, Zheng JC (2022) Astrocytes: GABAceptive and GABAergic Cells in the Brain. Front Cell Neurosci 16. s://doi.org/10.3389/fncel.2022.892497

Ishibashi M, Egawa K, Fukuda A (2019) Diverse Actions of Astrocytes in GABAergic Signaling. Int J Mol Sci 20:2964. s://doi.org/10.3390/ijms20122964

Anlauf E, Derouiche A (2013) Glutamine Synthetase as an Astrocytic Marker: Its Cell Type and Vesicle Localization. Front Endocrinol (Lausanne) 4. s://doi.org/10.3389/fendo.2013.00144

Eid T, Behar K, Dhaher R, Bumanglag A V., Lee T-SW (2012) Roles of Glutamine Synthetase Inhibition in Epilepsy. Neurochem Res 37:2339–2350. s://doi.org/10.1007/s11064-012-0766-5

Bernstein H-G, Tausch A, Wagner R, Steiner J, Seeleke P, Walter M, Dobrowolny H, Bogerts B (2013) Disruption of Glutamate-Glutamine-GABA Cycle Significantly Impacts on Suicidal Behaviour: Survey of the Literature and Own Findings on Glutamine Synthetase. CNS Neurol Disord - Drug Targets 12:900–913. s://doi.org/10.2174/18715273113129990091

Lee TS, Eid T, Mane S, Kim JH, Spencer DD, Ottersen OP, de Lanerolle NC (2004) Aquaporin-4 is increased in the sclerotic hippocampus in human temporal lobe epilepsy. Acta Neuropathol 108:493–502. s://doi.org/10.1007/s00401-004-0910-7

Binder DK, Yao X, Zador Z, Sick TJ, Verkman AS, Manley GT (2006) Increased seizure duration and slowed potassium kinetics in mice lacking aquaporin-4 water channels. Glia 53:631–636. s://doi.org/10.1002/glia.20318