Bi-directional genetic modulation of GSK-3β exacerbates hippocampal neuropathology in experimental status epilepticus

Autor: Takanori Sano, José J. Lucas, Félix Hernández, Alberto Rodríguez-Matellán, Eva M. Jimenez-Mateos, Miguel Medina, Mark Dunleavy, Tobias Engel, David C. Henshall, Raquel Gómez-Sintes, Marta Fernández-Nogales, James Morgan, Mariana Alves, Jesús Avila, Amaya Sanz-Rodriguez, Edward Beamer
Přispěvatelé: Health Research Board (Ireland), Science Foundation Ireland, Ministerio de Economía y Competitividad (España), European Commission, Fundación Ramón Areces, Fundación Banco Santander, Engel, Tobías [0000-0001-9137-0637], Beamer, Edward [0000-0003-1947-7346], Dunleavy, Mark [0000-0001-5916-9722], Medina, Miguel [0000-0002-7016-5340], Lucas, José Javier [0000-0003-1597-3916], Engel, Tobías, Beamer, Edward, Dunleavy, Mark, Medina, Miguel, Lucas, José Javier
Rok vydání: 2018
Předmět:
Zdroj: Cell Death and Disease, Vol 9, Iss 10, Pp 1-14 (2018)
Digital.CSIC. Repositorio Institucional del CSIC
instname
Cell Death & Disease
ISSN: 2041-4889
Popis: 14 p.-5 fig.
Glycogen synthase kinase-3 (GSK-3) is ubiquitously expressed throughout the brain and involved in vital molecular pathways such as cell survival and synaptic reorganization and has emerged as a potential drug target for brain diseases. A causal role for GSK-3, in particular the brain-enriched GSK-3β isoform, has been demonstrated in neurodegenerative diseases such as Alzheimer's and Huntington's, and in psychiatric diseases. Recent studies have also linked GSK-3 dysregulation to neuropathological outcomes in epilepsy. To date, however, there has been no genetic evidence for the involvement of GSK-3 in seizure-induced pathology. Status epilepticus (prolonged, damaging seizure) was induced via a microinjection of kainic acid into the amygdala of mice. Studies were conducted using two transgenic mouse lines: a neuron-specific GSK-3β overexpression and a neuron-specific dominant-negative GSK-3β (GSK-3β-DN) expression in order to determine the effects of increased or decreased GSK-3β activity, respectively, on seizures and attendant pathological changes in the hippocampus. GSK-3 inhibitors were also employed to support the genetic approach. Status epilepticus resulted in a spatiotemporal regulation of GSK-3 expression and activity in the hippocampus, with decreased GSK-3 activity evident in non-damaged hippocampal areas. Consistent with this, overexpression of GSK-3β exacerbated status epilepticus-induced neurodegeneration in mice. Surprisingly, decreasing GSK-3 activity, either via overexpression of GSK-3β-DN or through the use of specific GSK-3 inhibitors, also exacerbated hippocampal damage and increased seizure severity during status epilepticus. In conclusion, our results demonstrate that the brain has limited tolerance for modulation of GSK-3 activity in the setting of epileptic brain injury. These findings caution against targeting GSK-3 as a treatment strategy for epilepsy or other neurologic disorders where neuronal hyperexcitability is an underlying pathomechanism.
This work was supported by funding from the Sixth Framework Programme (MIRG-CT-2004-014567, to D.C.H.) a IRCSET-Marie Curie International Mobility Fellowship, the Health Research Board (PD/2009/31 to T.E. and HRA_POR/ 2011/41 to D.C.H.); Science Foundation Ireland (13/SIRG/2098 and 17/CDA/ 4708 to T.E. and 16/RC/3948 to D.C.H.) and co-funded under the European Regional Development Fund and by FutureNeuro industry partners;); from the H2020 Marie Skłowdowksa-Curie Actions Individual Fellowship (753527 to E.B.); from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklowdowska-Cuire grant agreement (No. 766124 to T.E.); grants from Ministerio de Economía Industria y Competitividad of Spain SAF2009-08233 and SAF2015-65371-R to J.J.L., SAF2016-78603-R to M.M. and BFU2016-77885-P to F.H.; grant PI2015-2/06-3 from CIBERNED-ISCIII to J.J.L.; and institutional grants to CBMSO from Fundación Ramón Areces and Fundación Banco de Santander.
Databáze: OpenAIRE
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