TY - JOUR
T1 - Activity-dependent p25 generation regulates synaptic plasticity and aβ-induced cognitive impairment
AU - Seo, Jinsoo
AU - Giusti-Rodríguez, Paola
AU - Zhou, Ying
AU - Rudenko, Andrii
AU - Cho, Sukhee
AU - Ota, Kristie T.
AU - Park, Christine
AU - Patzke, Holger
AU - Madabhushi, Ram
AU - Pan, Ling
AU - Mungenast, Alison E.
AU - Guan, Ji Song
AU - Delalle, Ivana
AU - Tsai, Li Huei
N1 - 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.
PY - 2014/4/10
Y1 - 2014/4/10
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2014.01.065
DO - 10.1016/j.cell.2014.01.065
M3 - Article
C2 - 24725413
AN - SCOPUS:84898603240
SN - 0092-8674
VL - 157
SP - 486
EP - 498
JO - Cell
JF - Cell
IS - 2
ER -