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TitleConditional disruption of calpain in the CNS alters dendrite morphology, impairs LTP, and promotes neuronal survival following injury.
Publication TypeJournal Article
Year of Publication2013
AuthorsAmini, Mandana, Chun-lei Ma, Rasoul Farazifard, Guoqi Zhu, Yi Zhang, Jacqueline Vanderluit, Joanna Susie Zoltewicz, Fadi Hage, Joseph M. Savitt, Diane C. Lagace, Ruth S. Slack, Jean-Claude Béïque, Michel Baudry, Peter A. Greer, Richard Bergeron, and David S. Park
JournalJ Neurosci
Date Published2013 Mar 27
Keywords1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Age Factors, alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid, Analysis of Variance, Animals, Animals, Newborn, Biophysics, Brain, Brain Injuries, Bromodeoxyuridine, Calpain, Cell Death, Dendrites, Disease Models, Animal, Electric Stimulation, Embryo, Mammalian, Evoked Potentials, Excitatory Amino Acid Agonists, Excitatory Postsynaptic Potentials, Female, Gene Expression Regulation, Developmental, Green Fluorescent Proteins, Hippocampus, In Vitro Techniques, Intermediate Filament Proteins, Long-Term Potentiation, Male, Maze Learning, Mice, Mice, Inbred C57BL, Mice, Transgenic, N-Methylaspartate, Nerve Tissue Proteins, Nestin, Neurons, Patch-Clamp Techniques, Phosphotransferases, Psychomotor Performance, RNA, Messenger, Silver Staining, Transfection, Tyrosine 3-Monooxygenase

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.

Alternate JournalJ. Neurosci.
PubMed ID23536090
PubMed Central IDPMC4153560
Grant ListP01 NS045260 / NS / NINDS NIH HHS / United States
P01NS045260-01 / NS / NINDS NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada