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The Journal of Neuroscience, December 6, 2006, 26(49):12700-12707; doi:10.1523/JNEUROSCI.2743-06.2006

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Behavioral/Systems/Cognitive
Transgenic Inhibition of Neuronal Protein Kinase A Activity Facilitates Fear Extinction

Carolina Isiegas,¹ Alice Park,² Eric R. Kandel,³ Ted Abel,¹ and K. Matthew Lattal⁴

¹Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, ²Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06250, ³Center for Neurobiology and Behavior and Howard Hughes Medical Institute, College of Physicians and Surgeons, Columbia University, New York, New York 10032, and ⁴Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, Oregon 97239

Correspondence should be addressed to either of the following: Carolina Isiegas at the above address, Email: cisiegas{at}sas.upenn.edu; or K. Matthew Lattal at the above address, Email: lattalm{at}ohsu.edu

Much is known about the neurobiology of memory storage for learned fear. In contrast, the molecular mechanisms underlying extinction of fear memory are just beginning to be delineated. Here, we investigate the role of protein kinase A (PKA) in extinction of memory for contextual fear by using conventional and temporally regulated transgenic approaches that allow us to inhibit PKA activity in neurons within brain regions thought to be involved in extinction. Strikingly, reduction of PKA activity facilitated the development of extinction, without interfering with storage of the original fear memory. Moreover, inhibition of PKA facilitated extinction of both recent and remote contextual fear memories. The finding that PKA, which is required for the acquisition of fear memory, is a constraint for extinction provides the first genetic support for the idea that fear extinction is itself a genuine learning process with its own specific molecular requirements, rather than simply the erasure of a previously learned process. Further, these experiments represent the first genetic evidence that protein kinases may be constraints for the extinction of fear.

Key words: reconsolidation; extinction; fear; learning memory; pavlovian conditioning; protein kinase; protein synthesis; tetracycline; transgenic

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Received June 27, 2006; revised Oct. 3, 2006; accepted Oct. 4, 2006.

Correspondence should be addressed to either of the following: Carolina Isiegas at the above address, Email: cisiegas{at}sas.upenn.edu; or K. Matthew Lattal at the above address, Email: lattalm{at}ohsu.edu

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