title: A pharmacogenetic inducible approach to the study of NMDA/alphaCaMKII signaling in synaptic plasticity.
abstract: We recently introduced an inducible pharmacogenetic approach where pharmacological manipulations can be used to reveal recessive mutant phenotypes in a temporally controlled manner. This approach takes advantage of synergisms between pharmacological and genetic manipulations to alter the function of specific signaling pathways. For example, mice heterozygous for a point mutation (T286A) in the alpha-calcium/calmodulin-dependent kinase II (alphaCaMKII) gene show normal learning and memory. However, a concentration of an NMDA receptor antagonist (CPP) that does not affect learning in wild-type (WT) littermates, reveals learning deficits in this heterozygote (alphaCaMKII(T286A+/-)). Here, we show that pretetanic application of a concentration of CPP (0.1 microM) ineffective in WT hippocampal slices induced deficits in alphaCaMKII(T286A+/-) slices in hippocampal long-term potentiation (LTP), a mechanism thought to be involved in learning and memory. Importantly, posttetanic application of CPP (0.1 microM) had no effect on the expression or maintenance of LTP in hippocampal slices from alphaCaMKII(T286A+/-) mice. Thus, this pharmacogenetic approach allowed us to demonstrate that NMDA receptor-dependent autophosphorylation of alphaCaMKII is required during the induction but not maintenance of LTP. This ability to temporally induce recessive mutant phenotypes could be applicable to a broad range of problems and genetic systems.
authors.affiliation: Department of Neurobiology, Brain Research Institute, University of California, Los Angeles 90095-1761, USA.
authors.forename: Masuo
authors.initials: M
authors.lastname: Ohno
authors.forename: Paul W
authors.initials: PW
authors.lastname: Frankland
authors.forename: Alcino J
authors.initials: AJ
authors.lastname: Silva
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D004594:Electrophysiology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects; D051379:Mice; D016202:N-Methylaspartate / Q000378:metabolism*; D010597:Pharmacogenetics / Q000379:methods*; D010879:Piperazines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*
chemical_list: D010879:Piperazines; D016202:N-Methylaspartate; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases