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The Journal of Neuroscience, July 9, 2003, 23(14):6005-6012

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Hippocampal cGMP-Dependent Protein Kinase I Supports an Age- and Protein Synthesis-Dependent Component of Long-Term Potentiation But Is Not Essential for Spatial Reference and Contextual Memory

Thomas Kleppisch,¹ Wiebke Wolfsgruber,¹ Susanne Feil,¹ Rüdiger Allmann,¹ Carsten T. Wotjak,² Sandra Goebbels,³ Klaus-Armin Nave,³ Franz Hofmann,¹ and Robert Feil¹

¹Institut für Pharmakologie und Toxikologie, 80802 München, Germany, ²Max-Planck-Institut für Psychiatrie, 80804 München, Germany, and ³Max-Planck-Institut für Experimentelle Medizin, 37075 Göttingen, Germany

cGMP-dependent protein kinase I (cGKI) is expressed in the hippocampus, but its role in hippocampal long-term potentiation (LTP) is controversial. In addition, whether cGKI is involved in spatial learning has not been investigated. To address these issues, we generated mice with a hippocampus-specific deletion of cGKI (cGKI^hko mice). Unlike conventional cGKI knock-out mice, cGKI^hko mice lack gastrointestinal and cardiovascular phenotypes and have a normal life expectancy, which enables us to analyze hippocampal synaptic plasticity and learning in young and adult animals. Hippocampal LTP after repetitive episodes of theta burst stimulation was impaired in adult (12–14 weeks of age) but not in juvenile (3–4 weeks of age) cGKI^hko mice. The difference in LTP between adult control and cGKI^hko mice was abolished by the protein synthesis inhibitor anisomycin, suggesting that the impairment of LTP in adult cGKI^hko mice reflects a defect in late-phase LTP. Despite their deficit in LTP, adult cGKI^hko mutants showed normal performance in a discriminatory water maze and had intact contextual fear conditioning. These results suggest that hippocampal cGKI supports an age- and protein synthesis-dependent form of hippocampal LTP, whereas it is dispensable for hippocampus-dependent spatial reference and contextual memory.

Key words: cGMP-kinase; conditional knockout; Cre recombinase; long-term potentiation; hippocampus; spatial learning; fear conditioning

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Received Dec. 9, 2002; revised Apr. 1, 2003; accepted Apr. 4, 2003.

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