University of Massachusetts Medical School Faculty Publications

UMMS Affiliation

Program in Molecular Medicine; Davis Lab; Graduate School of Biomedical Sciences; UMass Metabolic Network

Publication Date

2018-04-11

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Cell Biology | Cellular and Molecular Physiology | Developmental Biology | Enzymes and Coenzymes | Molecular and Cellular Neuroscience | Molecular Biology

Abstract

The c-Jun N-terminal kinase (JNK) signal transduction pathway is implicated in learning and memory. Here, we examined the role of JNK activation mediated by the JIP1 scaffold protein. We compared male wild-type mice with a mouse model harboring a point mutation in the Jip1 gene that selectively blocks JIP1-mediated JNK activation. These male mutant mice exhibited increased NMDA receptor currents, increased NMDA receptor-mediated gene expression, and a lower threshold for induction of hippocampal long-term potentiation. The JIP1 mutant mice also displayed improved hippocampus-dependent spatial memory and enhanced associative fear conditioning. These results were confirmed using a second JIP1 mutant mouse model that suppresses JNK activity. Together, these observations establish that JIP1-mediated JNK activation contributes to the regulation of hippocampus-dependent, NMDA receptor-mediated synaptic plasticity and learning. SIGNIFICANCE STATEMENT: The results of this study demonstrate that JNK activation induced by the JIP1 scaffold protein negatively regulates the threshold for induction of long-term synaptic plasticity through the NMDA-type glutamate receptor. This change in plasticity threshold influences learning. Indeed, mice with defects in JIP1-mediated JNK activation display enhanced memory in hippocampus-dependent tasks, such as contextual fear conditioning and Morris water maze, indicating that JIP1-JNK constrains spatial memory. This study reports the identification of JIP1-mediated JNK activation as a novel molecular pathway that negatively regulates NMDA receptor-dependent synaptic plasticity and memory.

Keywords

JIP1, JNK, LTP, fear, memory, plasticity

Rights and Permissions

Copyright © 2018 the authors. Publisher PDF posted after 6 months as allowed by the publisher's author rights policy at http://www.jneurosci.org/sites/default/files/files/JN_License_to_Publish.pdf.

DOI of Published Version

10.1523/JNEUROSCI.1913-17.2018

Source

J Neurosci. 2018 Apr 11;38(15):3708-3728. doi: 10.1523/JNEUROSCI.1913-17.2018. Epub 2018 Mar 14. Link to article on publisher's site

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

The Journal of neuroscience : the official journal of the Society for Neuroscience

PubMed ID

29540552

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