JIP1-Mediated JNK Activation Negatively Regulates Synaptic Plasticity and Spatial Memory
Kennedy, Norman J.
Forest, Kelly H.
Standen, Claire L.
Nichols, Robert A.
Davis, Roger J.
UMass Chan AffiliationsUMass Metabolic Network
Graduate School of Biomedical Sciences
Program in Molecular Medicine
Document TypeJournal Article
Amino Acids, Peptides, and Proteins
Cellular and Molecular Physiology
Enzymes and Coenzymes
Molecular and Cellular Neuroscience
MetadataShow full item record
AbstractThe 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.
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
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/29261
RightsCopyright © 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.