Neurogranin/RC3 enhances long-term potentiation and learning by promoting calcium-mediated signaling

In neurons, neurogranin (Ng) binds calmodulin (CaM), and its binding affinity is reduced by increasing Ca2+, phosphorylation by PKC, or oxidation by oxidants. Ng concentration in the hippocampus of adult mice varied broadly (Ng(+/+), similar to160-370 and Ng(+/-), similar to70-230 pmol/mg); the level in Ng(+/+) mice is one of the highest among all neuronal CaM-binding proteins. Among Ng(+/-) mice, but less apparent in Ng(+/+), a significant relationship existed between their hippocampal levels of Ng and performances in the Morris water maze. Ng(-/-) mice performed poorly in this task; they also displayed deficits in high-frequency-induced long-term potentiation (LTP) in area CA1 of hippocampal slices, whereas low-frequency-induced long-term depression was enhanced. Thus, compared with Ng(+/+) mice, the frequency-response curve of Ng(-/-) shifted to the right. Paired-pulse facilitation and synaptic fatigue during prolonged stimulation at 10 Hz (900 pulses) were unchanged in Ng(-/-) slices, indicating their normal presynaptic function. Measurements of Ca2+ transients in CA1 pyramidal neurons after weak and strong tetanic stimulations (100 Hz, 400 and 1000 msec, respectively) revealed a significantly greater intracellular Ca2+([Ca2+](i)) response in Ng(+/+) compared with Ng(-/-) mice, but the decay time constants did not differ. The diminished Ca2+ dynamics in Ng(-/-) mice are a likely cause of their decreased propensity to undergo LTP. Thus, Ng may promote a high [Ca2+](i) by a mass-action mechanism; namely, the higher the Ng concentration, the more Ng-CaM complexes will be formed, which effectively raises [Ca2+](i) at any given Ca2+ influx. This mechanism provides potent signal amplification in enhancing synaptic plasticity as well as learning and memory.