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
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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 C, Sherrin T, Kennedy NJ, Forest KH, Barutcu S, Robles M, Carpenter-Hyland E, Alfulaij N, Standen CL, Nichols RA, Benveniste M, Davis RJ, Todorovic C. (2018). JIP1-Mediated JNK Activation Negatively Regulates Synaptic Plasticity and Spatial Memory. UMass Chan Medical School Faculty Publications. https://doi.org/10.1523/JNEUROSCI.1913-17.2018. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1492
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