Conditional disruption of calpain in the CNS alters dendrite morphology, impairs LTP, and promotes neuronal survival following injury

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 ap...

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Bibliographic Details
Published in:The Journal of neuroscience 2013-03, Vol.33 (13), p.5773-5784
Main Authors: Amini, Mandana, Ma, Chun-lei, Farazifard, Rasoul, Zhu, Guoqi, Zhang, Yi, Vanderluit, Jacqueline, Zoltewicz, Joanna Susie, Hage, Fadi, Savitt, Joseph M, Lagace, Diane C, Slack, Ruth S, Beique, Jean-Claude, Baudry, Michel, Greer, Peter A, Bergeron, Richard, Park, David S
Format: Article
Language:English
Subjects:
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - pharmacology
Age Factors
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid - pharmacology
Analysis of Variance
Animals
Animals, Newborn
Biophysics
Brain - embryology
Brain - growth & development
Brain - pathology
Brain Injuries - chemically induced
Brain Injuries - metabolism
Brain Injuries - pathology
Brain Injuries - physiopathology
Bromodeoxyuridine - metabolism
Calpain - deficiency
Cell Death - drug effects
Cell Death - genetics
Dendrites - metabolism
Dendrites - pathology
Dendrites - ultrastructure
Disease Models, Animal
Electric Stimulation
Embryo, Mammalian
Evoked Potentials - drug effects
Evoked Potentials - physiology
Excitatory Amino Acid Agonists - pharmacology
Excitatory Postsynaptic Potentials - drug effects
Excitatory Postsynaptic Potentials - genetics
Female
Gene Expression Regulation, Developmental - genetics
Green Fluorescent Proteins - genetics
Hippocampus - cytology
In Vitro Techniques
Intermediate Filament Proteins - genetics
Intermediate Filament Proteins - metabolism
Long-Term Potentiation - genetics
Long-Term Potentiation - physiology
Male
Maze Learning - physiology
Mice
Mice, Inbred C57BL
Mice, Transgenic
N-Methylaspartate - pharmacology
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - metabolism
Nestin
Neurons - cytology
Neurons - metabolism
Patch-Clamp Techniques
Phosphotransferases
Psychomotor Performance
RNA, Messenger - metabolism
Silver Staining
Transfection
Tyrosine 3-Monooxygenase - genetics
Tyrosine 3-Monooxygenase - metabolism
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Summary: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.
ISSN:0270-6474
1529-2401
1529-2401
DOI:10.1523/jneurosci.4247-12.2013