HSP70 Facilitates Memory Consolidation of Fear Conditioning through MAPK Pathway in the Hippocampus

Abstract

Heat shock proteins of the 70-kDa (HSP70) family are cytoprotective molecular chaperones that are present in neuronal cells and can be induced by a variety of homeostatically stressful situations (not only proteostatic insults), but also by synaptic activity, including learning tasks. Physiological stimuli that induce long-term memory formation are also capable of stimulating the synthesis of HSP70 through the activation of heat shock transcription factor-1 (HSF1). In this study, we investigated the influence of HSP70 on fear memory consolidation and MAPK activity. Male rats were trained in contextual fear conditioning task and HSP70 content was analyzed by western blot in the hippocampus at different time points. We observed rapid and transient elevations in HSP70 60 min following training. Double immunofluorescence with GFAP and HSP72 revealed that astrocytes were not the site for HSP72 induction by CFC training. HSP72 distribution markedly surrounded synapses between Shaffer collateral and CA1 pyramidal cells. Infusion of recombinant HSP70 (hspa1a) into the dorsal hippocampus immediately after training facilitated memory consolidation and enhanced ERK activity while decreasing the activated forms of JNK and p38 in the hippocampus. Blocking endogenous extracellular HSP70 through the administration of specific antibody did not produce any further effect on memory consolidation when applied immediately after training, suggesting that it is indeed acting intracellularly. Induction of HSP70 after fear conditioning is fast and can act as a signaling molecule, modulating MAPK downstream signaling during memory consolidation in the hippocampus, which is crucial for fear memory formation.

Keywords: HSP70; MAPK; contextual fear conditioning; molecular chaperone.