Activity-dependent p25 generation regulates synaptic plasticity and aβ-induced cognitive impairment

Jinsoo Seo, Paola Giusti-Rodríguez, Ying Zhou, Andrii Rudenko, Sukhee Cho, Kristie T. Ota, Christine Park, Holger Patzke, Ram Madabhushi, Ling Pan, Alison E. Mungenast, Ji Song Guan, Ivana Delalle, Li Huei Tsai

Research output: Contribution to journalArticle

45 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)486-498
Number of pages13
JournalCell
Volume157
Issue number2
DOIs
StatePublished - Apr 10 2014

Fingerprint

Neuronal Plasticity
Plasticity
Cyclin-Dependent Kinase 5
Neurodegenerative diseases
Data storage equipment
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Phosphorylation
Calpain
Pathology
Amyloid
Alzheimer Disease
Neurodegenerative Diseases
Depression
Cognitive Dysfunction

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Seo, J., Giusti-Rodríguez, P., Zhou, Y., Rudenko, A., Cho, S., Ota, K. T., ... Tsai, L. H. (2014). Activity-dependent p25 generation regulates synaptic plasticity and aβ-induced cognitive impairment. Cell, 157(2), 486-498. https://doi.org/10.1016/j.cell.2014.01.065

Activity-dependent p25 generation regulates synaptic plasticity and aβ-induced cognitive impairment. / Seo, Jinsoo; Giusti-Rodríguez, Paola; Zhou, Ying; Rudenko, Andrii; Cho, Sukhee; Ota, Kristie T.; Park, Christine; Patzke, Holger; Madabhushi, Ram; Pan, Ling; Mungenast, Alison E.; Guan, Ji Song; Delalle, Ivana; Tsai, Li Huei.

In: Cell, Vol. 157, No. 2, 10.04.2014, p. 486-498.

Research output: Contribution to journalArticle

Seo, J, Giusti-Rodríguez, P, Zhou, Y, Rudenko, A, Cho, S, Ota, KT, Park, C, Patzke, H, Madabhushi, R, Pan, L, Mungenast, AE, Guan, JS, Delalle, I & Tsai, LH 2014, 'Activity-dependent p25 generation regulates synaptic plasticity and aβ-induced cognitive impairment', Cell, vol. 157, no. 2, pp. 486-498. https://doi.org/10.1016/j.cell.2014.01.065
Seo J, Giusti-Rodríguez P, Zhou Y, Rudenko A, Cho S, Ota KT et al. Activity-dependent p25 generation regulates synaptic plasticity and aβ-induced cognitive impairment. Cell. 2014 Apr 10;157(2):486-498. https://doi.org/10.1016/j.cell.2014.01.065
Seo, Jinsoo ; Giusti-Rodríguez, Paola ; Zhou, Ying ; Rudenko, Andrii ; Cho, Sukhee ; Ota, Kristie T. ; Park, Christine ; Patzke, Holger ; Madabhushi, Ram ; Pan, Ling ; Mungenast, Alison E. ; Guan, Ji Song ; Delalle, Ivana ; Tsai, Li Huei. / Activity-dependent p25 generation regulates synaptic plasticity and aβ-induced cognitive impairment. In: Cell. 2014 ; Vol. 157, No. 2. pp. 486-498.
@article{89fcd517e19347c9a44f975270c69931,
title = "Activity-dependent p25 generation regulates synaptic plasticity and aβ-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 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.",
author = "Jinsoo Seo and Paola Giusti-Rodr{\'i}guez and Ying Zhou and Andrii Rudenko and Sukhee Cho and Ota, {Kristie T.} and Christine Park and Holger Patzke and Ram Madabhushi and Ling Pan and Mungenast, {Alison E.} and Guan, {Ji Song} and Ivana Delalle and Tsai, {Li Huei}",
year = "2014",
month = "4",
day = "10",
doi = "10.1016/j.cell.2014.01.065",
language = "English (US)",
volume = "157",
pages = "486--498",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "2",

}

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

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.

UR - http://www.scopus.com/inward/record.url?scp=84898603240&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84898603240&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2014.01.065

DO - 10.1016/j.cell.2014.01.065

M3 - Article

VL - 157

SP - 486

EP - 498

JO - Cell

JF - Cell

SN - 0092-8674

IS - 2

ER -