Bi-directional genetic modulation of GSK-3β exacerbates hippocampal neuropathology in experimental status epilepticus
Year: 2018
Type: article
Abstract: 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.
Source: Cell Death and Disease
Institutions: Royal College of Surgeons in Ireland, Consejo Superior de Investigaciones Científicas, Biomedical Research Networking Center on Neurodegenerative Diseases, Centro de Investigación Biomédica en Red, Centro de Biología Molecular Severo Ochoa, Centro de Investigaciones Biológicas Margarita Salas, Universidad Autónoma de Madrid, Instituto de Salud Carlos III
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,990
Funders: Fundación Ramón Areces, Health Research Board, Centro de Biología Molecular Severo Ochoa, European Commission, Irish Research Council for Science, Engineering and Technology, Science Foundation Ireland, University College Dublin, Ministerio de Economía y Competitividad, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Horizon 2020 Framework Programme, Instituto de Salud Carlos III, Sixth Framework Programme, European Regional Development Fund
Awards: G1009109408, G1075250362, G1631881159, G1755389420, The ATP-gated purinergic P2X7 receptor as a novel target for the treatment of drug-refractory epilepsy, G1837504654, G1873075563, Interdisciplinary training network on the purinergic P2X7 receptor to control neuroinflammation and hyperexcitability in brain diseases., G2628364946, G2743672107, G434337789, G4445767003, The ATP-P2X7R axis: a target for drug-refractory epilepsy, G4937468798, G5543508765, FutureNeuro, G7128578356, G7218419251, Novel treatments and diagnostics for epilepsy via the ATP-gated P2X7 receptor, G7528503627, G8824911526, G883017994
OpenAlex ID: W2891355158