| The cAMP/PKA signaling pathway has been demonstrated to play a critical role in learning and memory. In neurons, PKA has a variety of substrates and responds to a number of stimuli. The regulatory mechanisms underlying the specificity and efficiency of PKA multivalent functions in neurons remain elusive. Studies have recently showed that PKA anchoring is required for several PKA-mediated biological processes. The transgenic mice carrying the inhibitor for PKA anchoring, Ht31, were generated and examined in memory tasks. The associations between PKA and protein phosphatases were disrupted in the hippocampus, amygdala and cortex of Ht31 transgenic mice. Hippocampal slices from Ht31 transgenic mice exhibited impairments in the long-lasting LTP. This is consistent with the results from the hippocampal slices treated with Ht31 peptides. Ht31 transgenic mice exhibited enhanced fear conditioning and object recognition memory, but showed impaired spatial memory in the hidden version of the Morris water maze. We further found that the enhanced fear conditioning was caused by the expression of the Ht31 transgene at the consolidation and retrieval, not the acquisition, of the memory formation. We also cloned a few AKAP clones from mouse cerebellum expression library, which were identified as known mouse AKAPs. Using the RII overlay assay, in situ hybridization and quantitative PCR, we investigated expression patterns of individual AKAPs throughout the mouse brain. In addition, we reported that one AKAP mutant mice exhibited impaired spatial memory but normal fear conditioning. We conclude that PKA anchoring plays an important role in learning and memory. It is reasonable to hypothesize that in different memory tasks, a distinct population of AKAPs or a unique individual AKAP is recruited to regulate PKA function, which results in discrete behavioral modulation as revealed by Ht31 transgenic mice. Further investigation of the molecular mechanisms of PKA anchoring in mouse brain will help better understanding the complexity of memory processing via different brain systems. |
