Regulation of synaptic and plasticity-related proteins by ryanodine receptors during epileptogenesis

• Ano de defesa: 2016
• Autor(a) principal: Rodriguez, Pedro Xavier Royero
• Orientador(a): Kihara, Alexandre Hiroaki
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: eng
• Instituição de defesa: Universidade Federal do ABC
• Programa de Pós-Graduação: Programa de Pós-Graduação em Neurociência e Cognição
• Link de acesso: http://biblioteca.ufabc.edu.br/index.php?codigo_sophia=79334&midiaext=71902; http://biblioteca.ufabc.edu.br/index.php?codigo_sophia=79334&midiaext=71902/index.php?codigo_sophia=79334&midiaext=71901

Status epilepticus (SE) is a clinical emergency that can lead to the development of temporal lobe epilepsy (TLE). The term epileptogenesis refers to the transformation of physiological neuronal networks into a dysfunctional state. In most patients presenting TLE, the development and maintenance of spontaneous seizures are linked with calcium (Ca+2)-dependent processes like neuronal loss, reactive gliosis and pathological neuronal plasticity. It has been shown that SE produces an increase in ryanodine receptor-dependent intracellular Ca+2 levels in hippocampal neurons, which remain elevated during the progression of the disease. In this context, the aim of this work was to investigate the effects of ryanodine receptors (RyRs) inhibition on the expression of important synaptic and plasticity-related proteins during the latent period of the pilocarpine model of TLE. First, we performed western blot and immunolabeling analyses in order to evaluate the pattern of distribution of the activity-regulated cytoskeleton-associated protein (ARC) in the rat hippocampus during the latent period. We observed decrease of the total protein levels 48 hours after SE, together with downregulation of its nuclear immunolabeling in granular cells of the dentate gyrus (DG). In addition, we observed the appearance of intense ARC immunoreactive neurons (IAINs) colocalizing mainly with excitatory neurons in CA1, CA3 and hilus. Intrahippocampal injections of the RyRs blocker dantrolene increased the total protein levels of the presynaptic protein synapsin I (SYN I) 48 hours after SE. We also observed up-regulation of SYN I and synaptophysin (SYP) in hippocampal regions known to receive important synaptic inputs. Finally, dantrolene showed neuroprotective effects by decreasing neuronal loss in CA1 and CA3 of experimental hippocampi. Our results suggest that ARC might be participating in the overall hippocampal reorganization and increase of excitability observed during epileptogenesis. In addition, RyRs may contribute to trigger the hippocampal neurodegeneration and synaptic alterations that lead to the development of acquired epilepsy.