Estudo da participação do receptor P2X7 no desempenho cognitivo de roedores: abordagens farmacológicas e genéticas

Abstract

A memória é um fenômeno decorrente de um conjunto de processos fisiológicos denominado plasticidade. Várias formas de plasticidade são necessárias no processo de formação da memória e também são responsáveis pelo gerenciamento do comportamento. O fenômeno eletrofisiológico chamado potencialização de longa duração (PLD), cuja ocorrência no hipocampo merece destaque, foi proposto como sendo o mecanismo de plasticidade constitutivo das bases da consolidação da memória nesta região encefálica. A importância da plasticidade na região CA1 do hipocampo se manifesta em diversas formas de aprendizado, como espacial e condicionamento clássico. Os eventos bioquímicos que culminam na plasticidade e formação da memória sofrem influência de diversos sistemas de neurotransmissores e evidências indicam também a participação do sistema purinérgico, provavelmente através dos receptores ionotrópicos P2X. Receptores purinérgicos do subtipo P2X7 (P2X7R), largamente distribuídos no sistema nervoso central (SNC), além de possuírem várias características que os distinguem de outros subtipos de receptores P2X, estão envolvidos na regulação da liberação de neurotransmissores cruciais para a promoção da PLD na região hipocampal e formação da memória. Assim, este trabalho objetivou avaliar a participação dos P2X7R em camundongos geneticamente modificados (KO), que não expressam o receptor P2X7, e ratos através da exposição destes a diferentes tarefas comportamentais, bem como avaliar o efeito do enriquecimento ambiental sobre possíveis déficits mnemônicos resultantes da supressão gênica sobre o receptor P2X7. Os resultados sugerem que os P2X7R participam tanto da memória aversiva como da memória espacial: o bloqueio farmacológico com o antagonista específico de P2X7R A-740003 em diferentes janelas temporais causou prejuízos mnemônicos em ratos submetidos à tarefa do medo condicionado contextual (MCC), enquanto a deleção do P2X7R causou déficits mnemônicos a camundongos nas tarefas do labirinto aquático de Morris e no MCC, indicando prejuízos nas memórias espacial e aversiva, respectivamente. Experimentos com enriquecimento ambiental sugerem que esta forma de estimulação contribui na reversão dos déficits mnemônicos causado pela ausência do P2X7R. Por fim, nenhuma alteração na memória de habituação foi observada em animais com deleção gênica para o P2X7R.

Memory is a phenomenon ensued by a set of physiological processes known as plasticity. Several forms of plasticity are necessary in the process of memory formation and are also responsible for the management of the behavior. The electrophysiological phenomenon called long-term potentiation (LTP), whose occurrence in the hippocampus is generally highlighted, was proposed to be the underlying plastic mechanism involved in the basis of memory consolidation in this brain region. The importance of plasticity in the CA1 region of the hippocampus is observed in several sorts of cognition, such as spatial learning and classic conditioning. The biochemical events that culminate in plasticity and memory formation are subject to the influence of several neurotransmission system and evidences suggest also the participation of the purinergic system in this process, likely through P2X receptors. Purinergic P2X7 ionotropic receptors (P2X7R), widely distributed through the central nervous system, possess a number of distinctive characteristics when compared to other P2X receptors and are involved in the regulation of the release of neurotransmitters that are crucial in the promotion of hippocampal LTP and memory formation. So, this work aimed to evaluate the participation of the P2X7R in genetically modified (KO) mice with suppressed expression of the P2X7R and rats through different behavioral paradigms, as well as to evaluate the effect of environmental enrichment on potential mnemonic deficits resulting from genetic suppression on the P2X7R. The results suggest that P2X7R participate on both aversive and spatial memory: pharmacological blockage with specific P2X7R antagonist A-740003 in different time-frames elicited mnemonic impairments in rats submitted to the contextual fear conditioning (CFC) task, and the deletion of P2X7R hampered both spatial and aversive memory of mice subjected to the Morris water maze and CFC paradigms, respectively. Experiments using mice subjected to environmental enrichment suggest that this form of stimulation reverses mnemonic impairments ascribed to the absence of P2X7R. Finally, no alterations were observed in the habituation memory of P2X7R KO mice.

Innovative studies carried out 50-30 years ago demonstrated that ATP plays a role in cell signaling. It was soon proposed that ATP activates ionotripic P2X, exerting influence on neurons as well as on glial cells. Also, ATP release has been implicated in hippocampal long term potentiation (LTP), whose molecular mechanisms in the hippocampal CA1 region are much alike those involved in the consolidation of long-term memory (LTM). Evidences show the presence of moderate-high expression of the P2X7 purinergic receptor (P2X7R) in presynaptic terminals in the central nervous system, mainly in hippocampal neurons, contributing to the modulation of neurotransmission in this region. This study aimed to investigate the participation of the P2X7R in genetically modified (KO) mice with suppressed expression of the P2X7R and rats through different behavioral paradigms, as well as to evaluate the effect of environmental enrichment on potential mnemonic deficits resulting from genetic suppression on the P2X7R. The results suggest that P2X7R participate on both aversive and spatial memory: pharmacological blockage with specific P2X7R antagonist A- 740003 in different time-frames elicited mnemonic impairments in rats submitted to the contextual fear conditioning (CFC) task, and the deletion of P2X7R hampered both spatial and aversive memory of mice subjected to the Morris water maze and CFC paradigms, respectively. Experiments using mice subjected to environmental enrichment suggest that this form of stimulation reverses mnemonic impairments ascribed to the absence of P2X7R. Finally, no alterations were observed in the habituation memory of P2X7R KO mice.