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Reprogramming Fear Memory through the Inhibition of GSK-3 during Reconsolidation
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Resumo(s)
A Perturbação de Stress Pós-Traumático (PSPT) é uma patologia psiquiátrica associada a um medo excessivo que atualmente afeta cerca de 7% da população ocidental. Apesar de se encontrarem disponíveis diversos tratamentos, nenhum deles conseguiu curar totalmente o medo desproporcionado associado à doença. As taxas de resposta à terapêutica são baixas e mais de 70% dos doentes não alcança remissão completa, destacando uma necessidade de investigação científica nesta área.
Este projeto visou a análise de abordagens terapêuticas que poderiam possivelmente levar à redução deste medo excessivo. Foram realizadas experiências de condicionamento do medo em murganhos que consistiram em etapas sequenciais de processamento da memória: aquisição, consolidação e reconsolidação. Durante a reconsolidação, a memória de uma experiência traumática é relembrada podendo eventualmente ser modificada, dando a esta etapa um elevado potencial terapêutico. A glicogénio sintase quinase-3 (GSK-3) é uma enzima ativa constitutivamente e expressa sob duas isoformas (GSK-3α e GSK-3β). Já demonstrou ter um papel importante no desenvolvimento de doenças neuropsiquiátricas. No entanto, até à data, poucos estudos foram conclusivos sobre uma relação direta entre a GSK-3 e a reconsolidação da memória. Assim, o trabalho teve como objetivo averiguar se a inibição da GSK-3 durante a reconsolidação poderia reprogramar o processamento da memória do medo.
Foram usados três inibidores: um inibidor seletivo da GSK-3β, TCS 2002, um inibidor seletivo da GSK-3α, SB 216763, e um inibidor não seletivo da GSK-3 α/β, BIO-Acetoxime. Dado que a GSK-3β é a isoforma expressa em maior quantidade no sistema nervoso central, esperávamos obter resultados mais evidentes usando o TCS. Inesperadamente, não houve redução significativa da resposta ao medo tanto com o TCS como com o SB, mas sim com a BIO. Em conclusão, a reconsolidação da memória do medo poderá ser destabilizada pelo bloqueio de ambas as isoformas da GSK-3, embora uma pesquisa mais aprofundada seja necessária.
Post-Traumatic Stress Disorder (PTSD) is one of the most common psychiatric disorders associated with excessive fear, affecting about 7% of Western population. Despite several treatments being currently available, none of them has yet succeeded in fully curing the excessive fear associated with this disease. Response rates are low and more than 70% of patients fail to achieve total remission. These odds clearly underline the need for further research and improvement in therapeutic options. This project focused on investigating possible therapeutic approaches to curb excessive fear, the main symptom of PTSD. To do so, fear conditioning experiments were carried out in mice. In this method mice undergo sequential stages of memory processing: acquisition, consolidation and reconsolidation. During reconsolidation, the memory of a traumatic experience is recalled and can eventually be modified, giving it a high therapeutic potential. Glycogen synthase kinase-3 (GSK-3) is a constitutively active kinase expressed in two isoforms (GSK-3α and GSK-3β) and is thought to play a role in the development of neuropsychiatric disorders. However, to date few studies have been conclusive about a direct relationship between GSK-3 and fear memory reconsolidation. Thus, the aim of our work was to ascertain whether the inhibition of GSK-3 was able to reprogram the processing of fear memories during reconsolidation. Three potent GSK-3 inhibitors were used: a selective GSK-3β inhibitor, TCS 2002, a selective GSK-3α inhibitor, SB 216763, and a non-selective GSK-3 α/β inhibitor, BIO-Acetoxime. Since GSK-3β is the most prevalent isoform in the central nervous system, we expected to see a stronger effect using TCS. Interestingly, results obtained showed no significant decrease in fear response either with TCS or SB, but a noticeable effect using BIO. In conclusion, fear memory reconsolidation may be disrupted by blockage of both GSK-3 isoforms, although further research in this field is still clearly necessary.
Post-Traumatic Stress Disorder (PTSD) is one of the most common psychiatric disorders associated with excessive fear, affecting about 7% of Western population. Despite several treatments being currently available, none of them has yet succeeded in fully curing the excessive fear associated with this disease. Response rates are low and more than 70% of patients fail to achieve total remission. These odds clearly underline the need for further research and improvement in therapeutic options. This project focused on investigating possible therapeutic approaches to curb excessive fear, the main symptom of PTSD. To do so, fear conditioning experiments were carried out in mice. In this method mice undergo sequential stages of memory processing: acquisition, consolidation and reconsolidation. During reconsolidation, the memory of a traumatic experience is recalled and can eventually be modified, giving it a high therapeutic potential. Glycogen synthase kinase-3 (GSK-3) is a constitutively active kinase expressed in two isoforms (GSK-3α and GSK-3β) and is thought to play a role in the development of neuropsychiatric disorders. However, to date few studies have been conclusive about a direct relationship between GSK-3 and fear memory reconsolidation. Thus, the aim of our work was to ascertain whether the inhibition of GSK-3 was able to reprogram the processing of fear memories during reconsolidation. Three potent GSK-3 inhibitors were used: a selective GSK-3β inhibitor, TCS 2002, a selective GSK-3α inhibitor, SB 216763, and a non-selective GSK-3 α/β inhibitor, BIO-Acetoxime. Since GSK-3β is the most prevalent isoform in the central nervous system, we expected to see a stronger effect using TCS. Interestingly, results obtained showed no significant decrease in fear response either with TCS or SB, but a noticeable effect using BIO. In conclusion, fear memory reconsolidation may be disrupted by blockage of both GSK-3 isoforms, although further research in this field is still clearly necessary.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2016
Palavras-chave
PTSD Memory Fear Conditioning Reconsolidation GSK-3 Mestrado Integrado - 2016