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The Journal of Neuroscience, November 24, 2004, 24(47):10660-10669; doi:10.1523/JNEUROSCI.2213-04.2004

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Behavioral/Systems/Cognitive
Neurogranin/RC3 Enhances Long-Term Potentiation and Learning by Promoting Calcium-Mediated Signaling

Kuo-Ping Huang,^1 * Freesia L. Huang,^1 * Tino Jäger,² Junfa Li,¹ Klaus G. Reymann,² and Detlef Balschun²

¹Section on Metabolic Regulation, Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-4510, and ²Leibniz Institute for Neurobiology, D-39008 Magdeburg, Germany

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^+/+, 160-370 and Ng^+/-, 70-230 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.

Key words: neurogranin; calmodulin; water maze; learning; LTP; calcium signaling

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Received June 7, 2004; revised September 9, 2004; accepted October 9, 2004.

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