Involvement of neurogranin in the modulation of calcium/calmodulin-dependent protein kinase II, synaptic plasticity, and spatial learning: A study with knockout mice

Neurogranin/RC3 is a neural-specific Ca2+-sensitive calmodulin (CaM)-bindin g protein whose Cam-binding affinity is modulated by phosphorylation and ox idation, Here we show that deletion of the Ng gene in mice did not result i n obvious developmental or neuroanatomical abnormalities but caused an impa irment of spatial learning and changes in hippocampal short- and long-term plasticity (paired-pulse depression, synaptic fatigue, long-term potentiati on induction). These deficits were accompanied by a decreased basal level o f the activated Ca2+/CaM-dependent kinase II (CaMKII) (approximate to 60% o f wild type). Furthermore, hippocampal slices of the mutant mice displayed a reduced ability to generate activated CaMKII after stimulation of protein phosphorylation and oxidation by treatments with okadaic acid and sodium n itroprusside, respectively. These results indicate a central role of Ng in the regulation of CaMKII activity with decisive influences on synaptic plas ticity and spatial learning.