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

نویسندگان

  • 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
چکیده

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.

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عنوان ژورنال:
  • The Journal of neuroscience : the official journal of the Society for Neuroscience

دوره 33 13  شماره 

صفحات  -

تاریخ انتشار 2013