The role of hippocampal signaling cascades in consolidation of fear memory.
We investigated the involvement of hippocampal protein kinase A (PKA), protein kinase C (PKC), calcium/calmodulin-dependent protein kinases (CaMK II), and mitogen-activated extracellular signal-regulated kinases 1 and 2 (Mek-1/2) in the phosphorylation of their downstream targets extracellular signal-regulated kinases 1 and 2 (Erk-1/2), cAMP-response element-binding protein (CREB), Elk-1, and p90 ribosomal S6 kinase 1 (p90Rsk-1). The role of these processes in memory consolidation of conditioned fear was determined. C57BL/6N mice were injected into the dorsal hippocampus with inhibitors of PKA, PKC, CaMK II, Mek-1/2, or vehicle before training consisting of a single exposure to a context, tone, and footshock. Freezing behavior of mice reflecting fear memory was scored after their re-exposure to the conditioned stimuli. Inhibition of PKA impaired context- and tone-dependent fear conditioning and significantly reduced the phosphorylation of Elk-1, p90Rsk-1, Erk-1/2, and CREB. PKC inhibition also impaired context- and tone-dependent fear conditioning and prevented the phosphorylation of Erk-1/2, Elk-1, and CREB, without affecting p90Rsk-1. Inhibition of CaMK II did not affect fear conditioning and reduced the phosphorylation of Erk-1/2, Elk-1, CREB, and p90Rsk-1 only transiently, whereas Mek-1/2 inhibition was ineffective in all experiments. It was concluded that hippocampal PKA and PKC play crucial roles in one-trial fear conditioning. Erk-1/2, Elk-1, and CREB were identified as common targets of PKA, PKC, and CaMK II during memory consolidation, however, the time window and sequence of their phosphorylation was specific for the individual kinase.
Ahi
Janak
J
Department of Molecular Neuroendocrinology, Max Planck Institute for Experimental Medicine, 37075, Goettingen, Germany.
Radulovic
Jelena
J
Spiess
Joachim
J
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism; D003213:Conditioning, Psychological / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005239:Fear / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D004791:Enzyme Inhibitors; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases