Program in Molecular Medicine; Davis Lab; Graduate School of Biomedical Sciences; UMass Metabolic Network
Amino Acids, Peptides, and Proteins | Cell Biology | Cellular and Molecular Physiology | Developmental Biology | Enzymes and Coenzymes | Molecular and Cellular Neuroscience | Molecular Biology
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.
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
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
The Journal of neuroscience : the official journal of the Society for Neuroscience
Morel, Caroline; Sherrin, Tessi; Kennedy, Norman J.; Forest, Kelly H.; Barutcu, Seda; Robles, Michael; Carpenter-Hyland, Ezekiel; Alfulaij, Naghum; Standen, Claire L.; Nichols, Robert A.; Benveniste, Morris; Davis, Roger J.; and Todorovic, Cedomir, "JIP1-Mediated JNK Activation Negatively Regulates Synaptic Plasticity and Spatial Memory" (2018). University of Massachusetts Medical School Faculty Publications. 1492.
Amino Acids, Peptides, and Proteins Commons, Cell Biology Commons, Cellular and Molecular Physiology Commons, Developmental Biology Commons, Enzymes and Coenzymes Commons, Molecular and Cellular Neuroscience Commons, Molecular Biology Commons