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Activity-dependent p25 generation regulates synaptic plasticity and A?-induced cognitive impairment.


ABSTRACT: Cyclin-dependent kinase 5 regulates numerous neuronal functions with its activator, p35. Under neurotoxic conditions, p35 undergoes proteolytic cleavage to liberate p25, which has been implicated in various neurodegenerative diseases. Here, we show that p25 is generated following neuronal activity under physiological conditions in a GluN2B- and CaMKII?-dependent manner. Moreover, we developed a knockin mouse model in which endogenous p35 is replaced with a calpain-resistant mutant p35 (?p35KI) to prevent p25 generation. The ?p35KI mice exhibit impaired long-term depression and defective memory extinction, likely mediated through persistent GluA1 phosphorylation at Ser845. Finally, crossing the ?p35KI mice with the 5XFAD mouse model of Alzheimer's disease (AD) resulted in an amelioration of ?-amyloid (A?)-induced synaptic depression and cognitive impairment. Together, these results reveal a physiological role of p25 production in synaptic plasticity and memory and provide new insights into the function of p25 in A?-associated neurotoxicity and AD-like pathology.

SUBMITTER: Seo J 

PROVIDER: S-EPMC4327772 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Cyclin-dependent kinase 5 regulates numerous neuronal functions with its activator, p35. Under neurotoxic conditions, p35 undergoes proteolytic cleavage to liberate p25, which has been implicated in various neurodegenerative diseases. Here, we show that p25 is generated following neuronal activity under physiological conditions in a GluN2B- and CaMKIIα-dependent manner. Moreover, we developed a knockin mouse model in which endogenous p35 is replaced with a calpain-resistant mutant p35 (Δp35KI) t  ...[more]

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