Papel dos receptores de adenosina e da PKA no prejuízo de memória causado pela privação de sono

• Ano de defesa: 2017
• Autor(a) principal: Oliveira, Sophia La Banca de [UNIFESP]
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de São Paulo (UNIFESP)
• Palavras-chave em Português: Memory; Sleep; Adenosine; Learning; Memória; Sono; Adenosina; Aprendizagem
• Link de acesso: https://sucupira.capes.gov.br/sucupira/public/consultas/coleta/trabalhoConclusao/viewTrabalhoConclusao.jsf?popup=true&id_trabalho=5225533; http://repositorio.unifesp.br/handle/11600/50409

Sleep deprivation (SD) impairs various cognitive functions, including different types of memory. Various neurotransmitters and neuromodulators signaling pathways are altered by SD, including adenosine signaling. Adenosine is a neuromodulator which acts as the main homeostatic regulator of sleep, its extracellular concentrations raise in various regions of the brain during SD. The behavioral effects of adenosine are dependent mainly on its actions on two receptors, the A1, a Gi protein coupled receptor, and A2A, a Gs protein coupled receptor. A1 receptor activation impairs memory formation, while the role of A2A receptor on memory formation is not well understood yet. Among the main intracellular signaling pathways modulated by adenosine are the protein kinase A (PKA) pathway and the exchange protein activated by cAMP (EPAC) pathway. Both enzimes are involved on the induction of long term potentiation (LTP), a cellular correlate of memory. Considering this background we suggest that adenosine has an important role in the memory impairment caused by SD through the activation of the adenosine receptors on the brain regions recruited during memory formation, such as the hippocampus and the striatum, and by consequent modulation of the PKA and EPAC pathways. To test this hypothesis we first evaluated the effect of 96 hours of SD through the multiple platform modified method on the levels of the A1 and A2A receptors on the hippocampus. We also used the phosphorylation of PKA to infer its activity. We observed that sleep deprivation decreased the levels of A2A receptor and phosphorylation of PKA, but had no effect on the A1 receptor levels. Then we tested the effect of DPCPX, an antagonist of the A1 receptor, on the performance of sleep deprived animals on two memory tasks, the multiple trial inhibitory avoidance (MTIA) and the contextual fear conditioning (CFC), and the effect of an A2A agonist, CGS 21680, and an A2A antagonist, ZM 241385, on the MTIA. The results showed that DPCPX prevented the impairment on the performance on the MTIA, but not on the CFC. While CGS 21680 had no effect on the performance on the MTIA, ZM 241385 impaired the xix performance of the control animals and increased the performance of the sleep deprived animals. We also tested the effect of SD and DPCPX on the levels of the A1 receptors in the phosphorylation of PKA and activation of EPAC in the striatum and hippocampus after the training session of the MTIA. SD increased the levels of A1 receptor on the striatum, but not in the hippocampus, DPCPX had no effect on neither structures. SD decreased PKA phosphorylation on both structures, DPCPX prevented this effect on the striatum, but not on the hippocampus. SD had no effect on the activity of EPAC. Finally, we tested the effect of drugs which act on other neurotransmitter systems on the phosphorylation of PKA on the hippocampus of animals subjected to the training session of the MTIA. We replicated the result that indicated a decrease on PKA phosphorylation and reverted it with the administration of d-ciclosserin, a NMDA coagonist. The alteration on the level of A2A receptors on the hippocampus and A1 receptors in the striatum indicates that SD has an impact on adenosine signaling on both structures. The activation of PKA on the hippocampus in the time interval between 30 minutes and 6 hours after the MTIA training session is necessary for memory consolidation. Its activation is also necessary for the LTP formation in the striatum. Thus, the decrease of the phosphorylation on these structures caused by SD after the MTIA training may be related to the effects of SD on memory. MTIA task has an instrumental component on which structures of the striatum are involved, this does not happen on the CFC, thus the effect of DPCPX on the MTIA, but not on the CFC may be related to the A1 receptors on the striatum, but not on the hippocampus. This result, as well as the increase on the levels of A1 receptors and the reversion of the decrease of PKA phosphorylation on the striatum indicate that the A1 receptors on the striatum have an important role on the performance impairment on MTIA caused by SD. On the other hand, DPCPX did not prevent the impairment on the CFC nor the decrease of the phosphorylation of PKA on the hippocampus, indicating that another neurotransmitter system would be involved on the impairment on this task. The reversion of the decrease of phosphorylation caused by the dciclosserin suggests an involviment of the NMDA receptors.