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

Mandana Amini, 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 Beique, Michel Baudry, Peter A. Greer, Richard Bergeron, David S. Park

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)5773-5784
Number of pages12
JournalJournal of Neuroscience
Volume33
Issue number13
DOIs
StatePublished - Mar 27 2013

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Calpain
Dendrites
Wounds and Injuries
Brain
Neuronal Plasticity
Cysteine Proteases
Long-Term Memory
Long-Term Potentiation

ASJC Scopus subject areas

  • Neuroscience(all)

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

In: Journal of Neuroscience, Vol. 33, No. 13, 27.03.2013, p. 5773-5784.

Research output: Contribution to journalArticle

Amini, M, Ma, CL, Farazifard, R, Zhu, G, Zhang, Y, Vanderluit, J, Zoltewicz, JS, Hage, F, Savitt, JM, Lagace, DC, Slack, RS, Beique, JC, Baudry, M, Greer, PA, Bergeron, R & Park, DS 2013, 'Conditional disruption of calpain in the CNS alters dendrite morphology, impairs LTP, and promotes neuronal survival following injury', Journal of Neuroscience, vol. 33, no. 13, pp. 5773-5784. https://doi.org/10.1523/JNEUROSCI.4247-12.2013
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. / Conditional disruption of calpain in the CNS alters dendrite morphology, impairs LTP, and promotes neuronal survival following injury. In: Journal of Neuroscience. 2013 ; Vol. 33, No. 13. pp. 5773-5784.
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AU - Lagace, Diane C.

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