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The Journal of Neuroscience, December 24, 2008, 28(52):14202-14212; doi:10.1523/JNEUROSCI.2216-08.2008

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Cellular/Molecular
Signaling through cGMP-Dependent Protein Kinase I in the Amygdala Is Critical for Auditory-Cued Fear Memory and Long-Term Potentiation

Cindy Paul,¹ Florian Schöberl,¹ Pascal Weinmeister,¹ Vincenzo Micale,^2,3 Carsten T. Wotjak,² Franz Hofmann,¹ and Thomas Kleppisch¹

¹Institut für Pharmakologie und Toxikologie, 80802 Munich, Germany, ²Max-Planck-Institut für Psychiatrie, 80804 Munich, Germany, and ³Department of Experimental and Clinical Pharmacology, University of Catania Medical School, 95125 Catania, Italy

Correspondence should be addressed to Dr. Thomas Kleppisch, Institut für Pharmakologie und Toxikologie, Biedersteiner Strasse 29, 80802 Munich, Germany. Email: kleppisch{at}ipt.med.tu-muenchen.de

Long-term potentiation (LTP) of inputs relaying sensory information from cortical and thalamic neurons to principal neurons in the lateral amygdala (LA) is thought to serve as a cellular mechanism for associative fear learning. Nitric oxide (NO), a messenger molecule widely implicated in synaptic plasticity and behavior, has been shown to enhance LTP in the LA as well as consolidation of associative fear memory. Additional evidence suggests that NO-induced enhancement of LTP and amygdala-dependent learning requires signaling through soluble guanylyl cyclase (sGC) and cGMP-dependent protein kinase (cGK). Mammals possess two genes for cGK: the prkg1 gene gives rise to the cGK type I isoforms, cGKI and cGKIβ, and the prkg2 gene encodes the cGK type II. Reportedly, both cGKI and cGKII are expressed in the amygdala, and cGKII is involved in controlling anxiety-like behavior. Because selective pharmacological tools for individual cGK isoforms are lacking, we used different knock-out mouse models to examine the function of cGKI and cGKII for LTP in the LA and pavlovian fear conditioning. We found robust expression of the cGKI specifically in the LA with cGKIβ as the prevailing isoform. We further show a marked reduction of LTP at both thalamic and cortical inputs to the LA and a selective impairment of auditory-cued fear memory in cGKI-deficient mutants. In contrast, cGKII null mutants lack these phenotypes. Our data suggest a function of cGKI, likely the β isoform, in the LA, supporting synaptic plasticity and consolidation of fear memory.

Key words: amygdala; cGMP; PKG; fear conditioning; long-term memory; long-term potentiation

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Received May 15, 2008; revised Nov. 6, 2008; accepted Nov. 6, 2008.

Correspondence should be addressed to Dr. Thomas Kleppisch, Institut für Pharmakologie und Toxikologie, Biedersteiner Strasse 29, 80802 Munich, Germany. Email: kleppisch{at}ipt.med.tu-muenchen.de

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