title: 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.
authors.affiliation: Cellular Molecular Medicine, School of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: Mandana
authors.initials: M
authors.lastname: Amini
authors.forename: Chun-lei
authors.initials: CL
authors.lastname: Ma
authors.forename: Rasoul
authors.initials: R
authors.lastname: Farazifard
authors.forename: Guoqi
authors.initials: G
authors.lastname: Zhu
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Vanderluit
authors.forename: Joanna Susie
authors.initials: JS
authors.lastname: Zoltewicz
authors.forename: Fadi
authors.initials: F
authors.lastname: Hage
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Savitt
authors.forename: Diane C
authors.initials: DC
authors.lastname: Lagace
authors.forename: Ruth S
authors.initials: RS
authors.lastname: Slack
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Beique
authors.forename: Michel
authors.initials: M
authors.lastname: Baudry
authors.forename: Peter A
authors.initials: PA
authors.lastname: Greer
authors.forename: Richard
authors.initials: R
authors.lastname: Bergeron
authors.forename: David S
authors.initials: DS
authors.lastname: Park
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001703:Biophysics; D001921:Brain / Q000196:embryology / Q000254:growth & development / Q000473:pathology; D001930:Brain Injuries / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D001973:Bromodeoxyuridine / Q000378:metabolism; D002154:Calpain / Q000172:deficiency*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D003712:Dendrites / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004622:Embryo, Mammalian; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism; D017774:Long-Term Potentiation / Q000235:genetics / Q000502:physiology*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016202:N-Methylaspartate / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D064231:Nestin; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010770:Phosphotransferases; D011597:Psychomotor Performance; D012333:RNA, Messenger / Q000378:metabolism; D016622:Silver Staining; D014162:Transfection; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: C492236:Cdk5r1 protein, mouse; D018690:Excitatory Amino Acid Agonists; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D012333:RNA, Messenger; C089495:neuronal Cdk5 activator (p25-p35); D049452:Green Fluorescent Proteins; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D010770:Phosphotransferases; D002154:Calpain; C410233:Capns1 protein, mouse; C570925:Capn2 protein, mouse; D001973:Bromodeoxyuridine
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