Calpain-1 and Calpain-2: The Yin and Yang of Synaptic Plasticity and Neurodegeneration

Baudry, Michel; Bi, Xiaoning

doi:10.1016/j.tins.2016.01.007

Cited by 194 publications

(192 citation statements)

References 88 publications

(93 reference statements)

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“…Members of the calpain family, however, have different targets and their activation results in a complex array of protein degradation with calpain 1 activation having predominantly neuroprotective effects whilst calpain 2 activation is neurotoxic [68,69]. These calpains may be activated to different degrees in different neuronal subtypes, perhaps explaining patterns of neuronal death in status epilepticus [69].…”

Section: Enzymes Activated By Intracellular Calcium Accumulationmentioning

confidence: 99%

Pathophysiology of status epilepticus

Walker¹

2018

Neuroscience Letters

104

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Status epilepticus (SE) is the maximal expression of epilepsy with a high morbidity and mortality. It occurs due to the failure of mechanisms that terminate seizures.Both human and animal data indicate that the longer a seizure lasts, the less likely it is to stop. Recent evidence suggests that there is a critical transition from an ictal to a post-ictal state, associated with a transition from a spatio-temporally desynchronized state to a highly synchronized state, respectively.As SE continues, it becomes progressively resistant to drugs, in particular benzodiazepines due partly to NMDA receptor-dependent internalization of GABA (A) receptors. Moreover, excessive calcium entry into neurons through excessive NMDA receptor activation results in activation of nitric oxide synthase, calpains, and NADPH oxidase. The latter enzyme plays a critical part in the generation of seizuredependent reactive oxygen species. Calcium also accumulates in mitochondria resulting in mitochondrial failure (decreased ATP production), and opening of the mitochondrial permeability transition pore. Together these changes result in status epilepticus-dependent neuronal death via several pathways. Multiple downstream mechanisms including inflammation, break down of the blood-brain barrier, and changes in gene expression can contribute to later pathological processes including chronic epilepsy and cognitive decline.

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Section: Enzymes Activated By Intracellular Calcium Accumulationmentioning

confidence: 99%

Pathophysiology of status epilepticus

Walker¹

2018

Neuroscience Letters

104

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“…However, we found that calpain activity was required 6 h after training to maintain LTM at 24 h. As protein synthesis is not required during this time frame for 24 h LFI memory (Levitan et al, 2010), we hypothesize that calpain activity 6 h post-training targets cytoskeletal proteins permitting synaptic expansion or the growth of new synapses. In mammals, dendritic proteins involved in actin cytoskeletal dynamics including spectrin, RhoA, Drebin, MARCSK are cleaved by calpains facilitating rearrangement of actin cytoskeleton networks and permitting synaptic growth (Baudry and Bi, 2016; Baudry et al, 2011; Baudry et al, 2013). Although long-term memory storage and synaptic growth may be dissociated as recently shown in Aplysia (Chen et al, 2014), synaptic remodeling and the growth of new synapses is considered an integral part of long-term memory stability (Bailey and Kandel, 2008; Kandel, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…At least 14 calpain isoforms and multiple splice variants have been identified in humans (Doshi and Lynch, 2009; Franco and Huttenlocher, 2005; Paquet-Durand et al, 2007; Suzuki et al, 2004; Ueyama et al, 1998; Wu and Lynch, 2006) with calpain-1 and calpain-2 the primary isoforms found in neurons (Baudry and Bi, 2016; Baudry et al, 2013; Briz and Baudry, 2016). Calpain-1 is more sensitive to calcium with in vitro activation occurring at micromolar concentrations while calpain-2 requires near millimolar concentrations of calcium for activation (Baudry and Bi, 2016; Jourdi, 2014). The role of calpains in memory was suggested more than three decades ago with neuronal calpain activity postulated as critical in translating post-synaptic calcium into long-term synaptic changes following the induction of long-term potentiation (Lynch and Baudry, 1984).…”

Section: Introductionmentioning

confidence: 99%

Differential role of calpain-dependent protein cleavage in intermediate and long-term operant memory in Aplysia

Lyons

Gardner

Lentsch

et al. 2017

Neurobiology of Learning and Memory

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In addition to protein synthesis, protein degradation or protein cleavage may be necessary for intermediate (ITM) and long-term memory (LTM) to remove molecular constraints, facilitate persistent kinase activity and modulate synaptic plasticity. Calpains, a family of conserved calcium dependent cysteine proteases, modulate synaptic function through protein cleavage. We used the marine mollusk Aplysia californica to investigate the in vivo role of calpains during intermediate and long-term operant memory formation using the learning that food is inedible (LFI) paradigm. A single LFI training session, in which the animal associates a specific netted seaweed with the failure to swallow, generates short (30 min), intermediate (4–6 hr) and long-term (24 hr) memory. Using the calpain inhibitors calpeptin and MDL-28170, we found that ITM requires calpain activity for induction and consolidation similar to the previously reported requirements for persistent protein kinase C activity in intermediate-term LFI memory. The induction of LTM also required calpain activity. In contrast to ITM, calpain activity was not necessary for the molecular consolidation of LTM. Surprisingly, six hours after LFI training we found that calpain activity was necessary for LTM, although this is a time at which neither persistent PKC activity nor protein synthesis is required for the maintenance of long-term LFI memory. These results demonstrate that calpains function in multiple roles in vivo during associative memory formation.

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“…Previous studies had indicated that PHLPP1 was truncated during learning, while its overexpression impaired learning, which was interpreted in the context of impairment of ERK activation under this condition (Shimizu et al 2007;Wang et al 2014;Baudry and Bi 2016). It was therefore predicted that PHLPP1 deletion would facilitate LTP induction and learning and memory.…”

Section: Discussionmentioning

confidence: 99%

Deleting both PHLPP1 and CANP1 rescues impairments in long-term potentiation and learning in both single knockout mice

et al. 2016

Self Cite

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Calpain-1 (CANP1) has been shown to play a critical role in synaptic plasticity and learning and memory, as its deletion in mice results in impairment in theta-burst stimulation-(TBS) induced LTP and various forms of learning and memory. Likewise, PHLPP1 (aka SCOP) has also been found to participate in learning and memory, as PHLPP1 overexpression impairs hippocampus-dependent learning. We previously showed that TBS-induced LTP was associated with calpain-1 mediated truncation of PHLPP1.To better understand the roles of these 2 genes in synaptic plasticity and learning and memory, we generated a double knockout (DKO) mouse by crossing the parent strains. Surprisingly, DKO mice exhibit normal TBS-induced LTP, and the learning impairments in fear conditioning and novel object or novel location recognition were absent in the DKO mice. Moreover, TBS-induced ERK activation in field CA1 of hippocampal slices, which is impaired in both single deletion mice, was restored in the DKO mice. These results further strengthen the roles of both CANP1 and PHLPP1 in synaptic plasticity and learning and memory, and illustrate the complexities of the interactions between multiple pathways participating in synaptic plasticity.While tremendous progress has been made regarding our understanding of the molecular/cellular mechanisms underlying learning and memory, many questions regarding the roles of various signaling pathways activated during learning remain unanswered Mehta 2015;Tonegawa et al. 2015;Smolen et al. 2016). In particular, while the calcium-dependent protease, calpain, has been proposed to participate in synaptic plasticity and learning and memory many years ago (Lynch and Baudry 1984), its precise contributions are still not clearly understood. This is in part due to the existence in the brain of two major calpain isoforms, calpain-1 (aka, m-calpain) and calpain-2 (aka, m-calpain), and the lack of tools to study their respective functions in synaptic plasticity. Our previous studies have shown that long-term potentiation (LTP) elicited by theta-burst stimulation (TBS), as well as learning of hippocampus-dependent tasks were impaired in calpain-1 knockout (CANP12/2) mice Liu et al. 2016). We also found that these impairments were related to the lack of calpain-1-mediated truncation of the PH domain and Leucine-rich repeat Protein Phosphatase 1 (PHLPP1, aka suprachiasmatic nucleus oscillatory protein (SCOP)) and the resulting stimulation of the extracellular signal-regulated kinase (ERK), which plays an important role in LTP induction and in learning and memory (Wang et al. 2014). On the other hand, calpain-2 activation was found to limit the extent of potentiation in hippocampal slices and learning of hippocampus-dependent tasks (Liu et al. 2016). It has previously been reported that PHLPP1 overexpression impairs learning and memory (Shimizu et al. 2007), suggesting that PHLPP1 could also participate in synaptic plasticity (Shimizu et al. 2010).To further evaluate the role of the calpain-1-mediated truncation of PHLPP1 i...

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Calpain-1 and Calpain-2: The Yin and Yang of Synaptic Plasticity and Neurodegeneration

Cited by 194 publications

References 88 publications

Pathophysiology of status epilepticus

Pathophysiology of status epilepticus

Differential role of calpain-dependent protein cleavage in intermediate and long-term operant memory in Aplysia

Deleting both PHLPP1 and CANP1 rescues impairments in long-term potentiation and learning in both single knockout mice

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