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 CaMKIIα-dependent manner. Moreover, we developed a knockin mouse model in which endogenous p35 is replaced with a calpain-resistant mutant p35 (Δp35KI) to prevent p25 generation. The Δp35KI mice exhibit impaired long-term depression and defective memory extinction, likely mediated through persistent GluA1 phosphorylation at Ser845. Finally, crossing the Δp35KI mice with the 5XFAD mouse model of Alzheimer's disease (AD) resulted in an amelioration of β-amyloid (Aβ)-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 Aβ-associated neurotoxicity and AD-like pathology.
| Original language | English |
|---|---|
| Pages (from-to) | 486-498 |
| Number of pages | 13 |
| Journal | Cell |
| Volume | 157 |
| Issue number | 2 |
| DOIs | |
| State | Published - 10 Apr 2014 |
Bibliographical note
Funding Information:We thank R. Neve for packaging the recombinant herpes simplex viruses; J. Giraud and E. Cornejo for early observations; Z. Xie for assistance in developing the cloning strategy to generate the Δp35KI mouse; W. Xu, S. Su, A. Nott, and A. Bero for helpful comments on the manuscript; and members of the Tsai lab for fruitful advice and discussions. We also thank M. Taylor for animal maintenance. This work was partially supported by the National Institutes of Health (grants R01 NS051874 to L.-H.T. and F31GM80055-03 to P.G.-R.) and the Howard Hughes Medical Institute.