Program in Molecular Medicine
Medical Subject Headings
Amino Acid Sequence; Amnesia; Animals; Anisomycin; Association Learning; Avoidance Learning; CA1 Region, Hippocampal; CA3 Region, Hippocampal; Down-Regulation; Female; Hippocampus; Isoenzymes; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinase 10; inhibitors; Mitogen-Activated Protein Kinase 8; inhibitors; Mitogen-Activated Protein Kinase 9; inhibitors; Molecular Sequence Data; Neurons; Protein Kinase Inhibitors; Stress, Psychological
Behavioral Neurobiology | Biochemistry | Cell Biology | Cellular and Molecular Physiology | Molecular and Cellular Neuroscience | Molecular Biology
In the adult mouse, signaling through c-Jun N-terminal kinases (JNKs) links exposure to acute stress to various physiological responses. Inflammatory cytokines, brain injury and ischemic insult, or exposure to psychological acute stressors induce activation of hippocampal JNKs. Here we report that exposure to acute stress caused activation of JNKs in the hippocampal CA1 and CA3 subfields, and impaired contextual fear conditioning. Conversely, intrahippocampal injection of JNKs inhibitors sp600125 (30 mum) or D-JNKI1 (8 mum) reduced activity of hippocampal JNKs and rescued stress-induced deficits in contextual fear. In addition, intrahippocampal administration of anisomycin (100 mug/mul), a potent JNKs activator, mimicked memory-impairing effects of stress on contextual fear. This anisomycin-induced amnesia was abolished after cotreatment with JNKs selective inhibitor sp600125 without affecting anisomycin's ability to effectively inhibit protein synthesis as measured by c-Fos immunoreactivity. We also demonstrated milder and transient activation of the JNKs pathway in the CA1 subfield of the hippocampus during contextual fear conditioning and an enhancement of contextual fear after pharmacological inhibition of JNKs under baseline conditions. Finally, using combined biochemical and transgenic approaches with mutant mice lacking different members of the JNK family (Jnk1, Jnk2, and Jnk3), we provided evidence that JNK2 and JNK3 are critically involved in stress-induced deficit of contextual fear, while JNK1 mainly regulates baseline learning in this behavioral task. Together, these results support the possibility that hippocampal JNKs serve as a critical molecular regulator in the formation of contextual fear.
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Citation: J Neurosci. 2010 Oct 6;30(40):13348-61. doi: 10.1523/JNEUROSCI.3492-10.2010. Link to article on publisher's site
Sherrin, Tessi; Blank, Thomas; Hippel, Cathrin; Rayner, Martin; Davis, Roger J.; and Todorovic, Cedomir, "Hippocampal c-Jun-N-terminal kinases serve as negative regulators of associative learning" (2010). Davis Lab. 27.
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