Alteration of the DSI of CA1 pyramidal neurons at the presence of pilocarpine and on the lithium-pilocarpine model of epilepsy

• Ano de defesa: 2023
• Autor(a) principal: Moradi, Marzieh
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: eng
• Instituição de defesa: Biblioteca Digitais de Teses e Dissertações da USP
• Palavras-chave em Português: CA1 pyramidal neurons; CB1R; Depolarization induced suppression of inhibition; Epilepsia; Epilepsy; Lithium-pilocarpine model of epilepsy; Modelo de epilepsia de lítio-pilocarpina; Neurônios piramidais CA1; Supressão de inibição induzida por despolarização
• Link de acesso: https://www.teses.usp.br/teses/disponiveis/17/17140/tde-08052023-142423/

Introduction: Epilepsy is one of the worlds oldest recognized disorder of the brain. About 30% of epileptic patients are suffering from the treatment resistant seizures, in which they are resistant to the clinically available anticonvulsants. One potential target for the development of new antiepileptic drugs is the endocannabinoid system which plays a central role in retrograde synaptic communication and may control the spread of activity in an epileptic network. Cannabinoid CB1 receptors are G-protein-coupled receptors that regulate neuronal excitability and have been shown to mediate acute anticonvulsant effects of cannabinoids in animal models. Depolarization-induced suppression of inhibition (DSI) is a form of endocannabinoid CB1 receptor-mediated inhibition of synaptic transmission. Objective: Despite the widespread interest and potential physiological importance of DSI, the alteration of this phenomena during seizure activities and status epilepticus (SE) induced by lithium-pilocarpine model has never been studied. Methods: Spontaneous GABAA receptor-mediated inhibitory postsynaptic currents (sIPSCs) were recorded prior to and following depolarization of CA1 hippocampal pyramidal cells; then we calculated the changes of DSI in two phases. First, patch clamp recordings of CA1 pyramidal neurons were performed in hippocampal slices incubated with pilocarpine, also registering DSI of the CA1 pyramidal neurons while they were being perfused by aCSF containing pilocarpine. Second, we performed patch clamp recordings of CA1 pyramidal neurons from pilocarpine-treated rats in different time points after the induction of SE. Results: The data showed that the amplitudes and frequencies of sIPSCs increased in response to incubating the slices with pilocarpine (10µM) and we found less DSI in these slices when we quantified the frequency of sIPSCs. However we did not find any effect of perfused pilocarpine (10µM) on the sIPSCs and on DSI, but a decrease in the amplitude and increased frequency of sIPCS after perfusion with 100 µM pilocarpine. Induction of SE, did not have any considerable effects on the amplitudes and frequencies of the sIPSC in none of the time points that we examined. However, the DSI of the amplitude decreased in rats immediately sacrificed after SE as well as 24 h after the SE, but the DSI of frequency increased after 24 hours. There were no changes in the DSI of neurons 1 week after SE. Discussion: We conclude that pilocarpine, depending on the dosage and the duration of application, has complex effects on GABAergic transmission in the CA1, enhancing it when present in the hippocampal slices and mostly decreasing DSI. And, the decreased in the DSI of CA1 pyramidal neurons found at 2 and 24 hours after SE, which might be related to the transient decrease in CB1Rs, is the primary compensatory response of the hippocampus to the increased level of excitation, which cannot be seen 1 week later.