title: cGMP-dependent protein kinase type I promotes CREB/CRE-mediated gene expression in neurons of the lateral amygdala.
abstract: The process transforming newly learned information into stable long-term memory is called memory consolidation and, like the underlying long-term synaptic plasticity, critically depends on de novo RNA and protein synthesis. We have shown recently that the cGMP-dependent protein kinase Type I (cGKI) plays an important role for the consolidation of amygdala-dependent fear memory and long-term potentiation (LTP) in the lateral amygdala. Signalling downstream of cGKI at the level of transcriptional regulation remained unclear. A transcription factor of major importance for learning and memory is the cAMP-response element binding protein (CREB). The representation of fear memory in the lateral amygdala strikingly depends on the activity of CREB in individual neurons. Moreover, findings from in vitro experiments demonstrate CREB phosphorylation by cGK. In the hippocampus, CREB phosphorylation increases following activation of NO/cGMP signalling contributing to the late phase of LTP. To demonstrate a link from cGKI to activation of CREB and CREB-dependent transcription in neurons of the lateral amygdala as a possible mechanism for cGKI-mediated fear memory consolidation, we examined the effect of cGMP on activation of CREB/CRE using immunohistochemical staining specific for phospho-CREB and a reporter gene in control and cGKI-deficient mice, respectively. Supporting our hypothesis, marked CREB phosphorylation and CRE-mediated transcription was induced by cGMP in the lateral amygdala of control mice, but not in cGKI-deficient mice. It has been proposed that activation of cGKI is followed by its nuclear translocation that would allow direct phosphorylation of CREB. Therefore, we examined the cellular localisation of cGKI in neurons of the lateral amygdala in the presence of cGMP by double staining for cGKI and a nuclear marker in sections from areas showing prominent CREB phosphorylation, and did not observe prominent nuclear translocation of the enzyme. In summary, we provide evidence that cytosolic cGKI can support fear memory consolidation and LTP in neurons of the lateral amygdala via activation of CREB and CRE-dependent transcription.
authors.affiliation: Institut für Pharmakologie und Toxikologie der Technischen Universität München, Biedersteiner Strasse 29, 80802 München, Germany.
authors.forename: Cindy
authors.initials: C
authors.lastname: Paul
authors.forename: Christopher
authors.initials: C
authors.lastname: Stratil
authors.forename: Franz
authors.initials: F
authors.lastname: Hofmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Kleppisch
mesh_terms: D000679:Amygdala / Q000378:metabolism*; D000818:Animals; D003213:Conditioning, Psychological; D017362:Cyclic AMP Response Element-Binding Protein / Q000096:biosynthesis / Q000502:physiology*; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases / Q000235:genetics / Q000502:physiology*; D005239:Fear; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D007150:Immunohistochemistry; D019426:Integrases / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases; C569720:Prkg1 protein, mouse; C045073:Cre recombinase; D019426:Integrases