Hippocampal calpain is required for the consolidation and reconsolidation but not extinction of contextual fear memory

Abstract

Memory consolidation, reconsolidation, and extinction have been shown to share similar molecular signatures, including new gene expression. Calpain is a Ca2+-dependent protease that exerts its effects through the proteolytic cleavage of target proteins. Neuron-specific conditional deletions of calpain 1 and 2 impair long-term potentiation in the hippocampus and spatial learning. Moreover, recent studies have suggested distinct roles of calpain 1 and 2 in synaptic plasticity. However, the role of hippocampal calpain in memory processes, especially memory consolidation, reconsolidation, and extinction, is still unclear. In the current study, we demonstrated the critical roles of hippocampal calpain in the consolidation, reconsolidation, and extinction of contextual fear memory in mice. We examined the effects of pharmacological inhibition of calpain in the hippocampus on these memory processes, using the N-Acetyl-Leu-Leu-norleucinal (ALLN; calpain 1 and 2 inhibitor). Microinfusion of ALLN into the dorsal hippocampus impaired long-term memory (24 h memory) without affecting short-term memory (2 h memory). Similarly, this pharmacological blockade of calpain in the dorsal hippocampus also disrupted reactivated memory but did not affect memory extinction. Importantly, the systemic administration of ALLN inhibited the induction of c-fos in the hippocampus, which is observed when memory is consolidated. Our observations showed that hippocampal calpain is required for the consolidation and reconsolidation of contextual fear memory. Further, the results suggested that calpain contributes to the regulation of new gene expression that is necessary for these memory processes as a regulator of Ca2+-signal transduction pathway.

Noninvasive Early Detection of Calpain 2-Enriched Non-Small Cell Lung Cancer Using a Human Serum Albumin-Bounded Calpain 2 Nanosensor

“…Increased local Ca 2+ amount and its influx enhance CAPN2 gene expression in tumor tissues. Previous studies have demonstrated that calpain inhibitors block Ca 2+ and signal transduction pathway. , …”

“…Previous studies have demonstrated that calpain inhibitors block Ca 2+ and signal transduction pathway. 31,32 Confirmation of Recovered Fluorescence Signals in Tumor Tissues. Further confirmation of HSA−CAPN2 target efficacy in tumor tissues, immunohistochemistry, and tissue clarity were performed.…”

Molecular mechanisms underpinning deconditioning‐update in fear memory

“…This Ca ++ ‐dependent protease is closely involved in the cytoskeleton remodeling that maintains the morphology of the dendritic spines (Lu et al, 2000; Simpkins et al, 2003; Wu & Lynch, 2006). Calpain modulates mnemonic processes such as consolidation, retrieval, and reconsolidation in rodents (Nagayoshi et al, 2017; Popik et al, 2018). Here, we reported that the calpain inhibitor PD150606 blocked the memory updating by deconditioning (Figure 3).…”

Functional Compartmentalization of the Contribution of Hippocampal Subfields to Context-Dependent Extinction Learning

“…Given its essential role in spatial, associative and context-dependent learning (for a review see McDonald and Mott, 2017), the hippocampus seems a likely location for the encoding of context-dependent extinction learning. Indeed, a specific role for the hippocampus in the extinction of conditioned aversive experience has been proposed (Vianna et al, 2003; Bouton et al, 2006; Herry et al, 2010; Orsini et al, 2011; Cleren et al, 2013; Chang et al, 2015; Nagayoshi et al, 2017). To what extent the hippocampus contributes to extinction learning of appetitive experience is less clear, although this seems likely (Conejo et al, 2013; Méndez-Couz et al, 2014, 2015b).…”