Conditional Disruption of Calpain in the CNS Alters Dendrite Morphology, Impairs LTP, and Promotes Neuronal Survival following Injury

Abstract

Ubiquitous classical (typical) calpains, calpain-1 and calpain-2, are Ca+2-dependent cysteine proteases, which have been associated with numerous physiological and pathological cellular functions. However, a clear understanding of the role of calpains in the CNS has been hampered by the lack of appropriate deletion paradigms in the brain. In this study, we describe a unique model of conditional deletion of both calpain-1 and calpain-2 activities in mouse brain, which more definitively assesses the role of these ubiquitous proteases in brain development/function and pathology. Surprisingly, we show that these calpains are not critical for gross CNS development. However, calpain-1/calpain-2 loss leads to reduced dendritic branching complexity and spine density deficits associated with major deterioration in hippocampal long-term potentiation and spatial memory. Moreover, calpain-1/calpain-2-deficient neurons were significantly resistant to injury induced by excitotoxic stress or mitochondrial toxicity. Examination of downstream target showed that the conversion of the Cdk5 activator, p35, to pathogenic p25 form, occurred only in the presence of calpain and that it played a major role in calpain-mediated neuronal death. These findings unequivocally establish two central roles of calpain-1/calpain-2 in CNS function in plasticity and neuronal death.

Calpain inhibitor, MDL 28170 confer electrophysiological, nociceptive and biochemical improvement in diabetic neuropathy

“…It may be that calpain activation is a downstream effect of many cellular injuries, including disrupted axonal transport that leads to cytoskeletal degradation, DNA fragmentation, apoptosis and ultimately cell death. Therefore, calpain inhibitors may serve a useful approach in neuroprotection in many neurological disorders (Amini et al, 2013;Baudry et al, 2013;Das et al, 2012;Huang and Wang, 2001;Ma et al, 2013;Samantaray et al, 2013aSamantaray et al, , 2013b. In the present study, we sought to explain the role of calpain activation with respect to alterations in TTX-R Na þ channel kinetics in diabetic neuropathy, which can form novel target for drug treatment in diabetic complications.…”

“…Though the function of calpain is not yet clear, it modulates a variety of physiological processes and remains important mediator of cell proliferation, differentiation, muscle contraction and apoptosis (Goll et al, 2003;Mattson, 2003;Neumar et al, 2003). Calpain is not 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 only involved in neuronal death via apoptosis cascade but also regulate synaptic plasticity and neural circuitry (Amini et al, 2013;Baudry et al, 2013). Calpain plays an active role in excitotoxicity caused by NMDA and AMPA receptor activation in hippocampal neurons and slice culture (Araujo et al, 2004;Bahr et al, 2002;Lankiewicz et al, 2000).…”

Erythropoietin attenuates loss of potassium chloride co-transporters following prenatal brain injury

“…Further, we show that erythropoietin (EPO) administration in a clinically useful postnatal post-injury paradigm protects the developing brain by restoring KCC2 expression, attenuating KCC2 fragmentation, and reducing calpain activity. While deficits in functional KCC2 membrane expression are detrimental to inhibitory tone and circuit refinement, efforts to modulate KCC2 levels via brain derived neurotrophic factor (BDNF) or calpain signal transduction have unexpected side effects and low therapeutic indices (Amini et al, 2013; Ferrini et al, 2013). Our results indicate KCC2 loss induced by preterm brain injury during a critical period of circuit development can be mitigated with neonatal EPO treatment.…”

Calpain Genetic Disruption and HSP90 Inhibition Combine To Attenuate Mammary Tumorigenesis

“…Paradoxically, calpain is associated with prodeath (8,9) or prosurvival (9-11), depending upon the physiologic context and specific challenges cells are exposed to. For example, calpain-mediated cleavage of PP2A supports activation of AKT and a prosurvival function in mouse embryonic fibroblasts (MEFs) (10), and in breast cancer cells and xenograft mouse models, knockdown of CAPN2 was associated with attenuated tumor growth and deregulation of the phosphatidylinositol 3-kinase (PI3K)-AKT-FoxO signaling axis (12).…”

“…For example, calpain-mediated cleavage of PP2A supports activation of AKT and a prosurvival function in mouse embryonic fibroblasts (MEFs) (10), and in breast cancer cells and xenograft mouse models, knockdown of CAPN2 was associated with attenuated tumor growth and deregulation of the phosphatidylinositol 3-kinase (PI3K)-AKT-FoxO signaling axis (12). In contrast, prodeath functions for calpain are suggested by resistance to specific apoptotic challenges in calpain-deficient neuronal cells (8). Thus, therapeutic benefits of calpain inhibition in cancer will depend upon the specific challenges faced by cancer cells.…”