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Background: Neurogranin/RC3 (Ng) is one of the most prominent PKC substrates concentrated in the post-synaptic terminals. It is also sensitive to modifications by oxidants, such as nitric oxide and hydrogen peroxide, to generate intramolecular disulfide bonds and/or glutathiolation. Both the phosphorylated and intramolecular disulfide forms of Ng have lower affinities for CaM as compared to that of the unmodified form. By virtue of its ability to bind CaM and to regulate the intracellular levels of calcium and CaM, Ng has been implicated in the regulation of many signal transduction pathways utilizing calcium, cAMP, and NO as second messengers. To investigate the role of Ng in neural function, we have generated a strain of knockout (KO) mice. The mutant mice develop normally without any obvious anatomical abnormality; however, they exhibit severe deficits in learning the spatial tasks. Analysis of the learning behaviors of the heterozygous and wild type mice revealed that the abilities of mice to learn the spatial tasks are positively correlated to their hippocampal Ng contents. The mutant mice also exhibit deficits in the induction and maintenance of long-term potentiation (LTP). The biochemical basis of these deficits appears to be related, in part, to the defective mechanism for the activation of CaMKII.
Ongoing research: Use Ng KO mice to study the regulatory roles of Ng in postsynaptic signal transduction pathways underlying neuronal plasticity, and learning and memory. Currently, we are investigating the neurotransmitter- and LTP-induced phosphorylation and upregulation of the various signaling components relevant to synaptic plasticity in both the wild type and KO mice. Cognitive functions of the mutant mice are being tested with several behavioral testing protocols to better understand the extent of deficits in the KO mice. We are also making attempt to generate transgenic mice to remedy the deficits of these KO mice.