RT Journal Article
SR Electronic
T1 Conditional Disruption of Calpain in the CNS Alters Dendrite Morphology, Impairs LTP, and Promotes Neuronal Survival following Injury
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 5773
OP 5784
DO 10.1523/JNEUROSCI.4247-12.2013
VO 33
IS 13
A1 Amini, Mandana
A1 Ma, Chun-lei
A1 Farazifard, Rasoul
A1 Zhu, Guoqi
A1 Zhang, Yi
A1 Vanderluit, Jacqueline
A1 Zoltewicz, Joanna Susie
A1 Hage, Fadi
A1 Savitt, Joseph M.
A1 Lagace, Diane C.
A1 Slack, Ruth S.
A1 Beique, Jean-Claude
A1 Baudry, Michel
A1 Greer, Peter A.
A1 Bergeron, Richard
A1 Park, David S.
YR 2013
UL http://www.jneurosci.org/content/33/13/5773.abstract
AB 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.