Calpastatin Overexpression Preserves Cognitive Function Following Seizures, While Maintaining Post-Injury Neurogenesis

Abstract

In the adult mammalian brain, new neurons continue to be produced throughout life in two main regions in the brain, the subgranular zone (SGZ) in the hippocampus and the subventricular zone in the walls of the lateral ventricles. Neural stem cells (NSCs) proliferate in these niches, and migrate as neuroblasts, to further differentiate in locations where new neurons are needed, either in normal or pathological conditions. However, the endogenous attempt of brain repair is not very efficient. Calpains are proteases known to be involved in neuronal damage and in cell proliferation, migration and differentiation of several cell types, though their effects on neurogenesis are not well known. Previous work by our group has shown that the absence of calpastatin (CAST), the endogenous inhibitor of calpains, impairs early stages of neurogenesis. Since the hippocampus is highly associated with learning and memory, we aimed to evaluate whether calpain inhibition would help improve cognitive recovery after lesion and efficiency of post-injury neurogenesis in this region. For that purpose, we used the kainic acid (KA) model of seizure-induced hippocampal lesion and mice overexpressing CAST. Selected cognitive tests were performed on the 3rd and 8th week after KA-induced lesion, and cell proliferation, migration and differentiation in the dentate gyrus (DG) of the hippocampus of adult mice were analyzed using specific markers. Cognitive recovery was evaluated by testing the animals for recognition, spatial and associative learning and memory. Cognitive function was preserved by CAST overexpression following seizures, while modulation of post-injury neurogenesis was similar to wild type (WT) mice. Calpain inhibition could still be potentially able to prevent the impairment in the formation of new neurons, given that the levels of calpain activity could be reduced under a certain threshold and other harmful effects from the pathological environment could also be controlled.

Nrdp1 is involved in hippocampus apoptosis in cardiopulmonary bypass-induced cognitive dysfunction via the regulation of ErbB3 protein levels

“…Certain studies have demonstrated that the information from vertebral cells in the hippocampus region may be projected into the cerebral cortex through the cerebral foot and fimbria of the fornix, forming connections among the neurons and a closed loop for learning and memory ( 21 , 22 ). In addition, cell proliferation, migration and differentiation in hippocampus were revealed to be closely associated with spatial and associative learning and memory ( 23 ). Apoptosis is a complex intracellular cascade, with multiple signals and pathways involved in the initiation of cellular apoptosis.…”

Pin1 Promotes Regulated Necrosis Induced by Glutamate in Rat Retinal Neurons via CAST/Calpain2 Pathway

“…Recent studies have addressed that CAST/calpain system was involved in cell death following glutamate excitotoxicity ( Miao et al, 2012 ; Curcio et al, 2015 ; Yan et al, 2016 ). Calpains are calcium-dependent cysteine proteases, which ubiquitously exist in organisms ( Curcio et al, 2016 ; Machado et al, 2017 ). The activity of calpains are physiologically regulated by its specific endogenous inhibitor, calpastatin (CAST) ( Averna et al, 2001 ; Volbracht et al, 2005 ).…”

Asiatic Acid Prevents Cognitive Deficits by Inhibiting Calpain Activation and Preserving Synaptic and Mitochondrial Function in Rats with Kainic Acid-Induced Seizure

“…Calpains are calcium-dependent proteases involved in neuronal death induced by KA [ 38 , 39 ]. Calpain inhibition through calpastatin, the endogenous inhibitor of calpains, can protect against KA-induced hippocampal neuronal damage and cognitive dysfunction [ 40 ]. Therefore, we examined the effect of asiatic acid on the expression of calpains and calpastatin in KA-treated rats.…”

“…In addition, KA treatment results in neuronal damage or death, with associated increased levels of calpains, which are ubiquitously expressed calcium-activated proteases [ 39 , 51 ]. Calpain inhibition has been demonstrated to improve neuronal function and limit neuronal damage in several excitotoxic brain injuries [ 38 , 40 , 44 ]. In the current study, we observed that KA treatment increased the level of calpains and reduced the level of calpastatin, a calpain inhibitor, in the hippocampus.…”