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The Journal of Neuroscience, July 12, 2006, 26(28):7337-7347; doi:10.1523/JNEUROSCI.0729-06.2006

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Cellular/Molecular
Role of the Neurogranin Concentrated in Spines in the Induction of Long-Term Potentiation

Anatol M. Zhabotinsky,^1,3 R. Nicholas Camp,² Irving R. Epstein,^1,3 and John E. Lisman^2,3

Departments of ¹Chemistry and ²Biology and ³Volen Center for Complex Systems, Brandeis University, Waltham, Massachusetts 02454-9110

Correspondence should be addressed to Dr. Anatol M. Zhabotinsky, Department of Chemistry, Brandeis University, Waltham, MA 02454-9110. Email: zhabotin{at}brandeis.edu

Synaptic plasticity in CA1 hippocampal neurons depends on Ca²⁺ elevation and the resulting activation of calmodulin-dependent enzymes. Induction of long-term depression (LTD) depends on calcineurin, whereas long-term potentiation (LTP) depends on Ca²⁺/calmodulin-dependent protein kinase II (CaMKII). The concentration of calmodulin in neurons is considerably less than the total concentration of the apocalmodulin-binding proteins neurogranin and GAP-43, resulting in a low level of free calmodulin in the resting state. Neurogranin is highly concentrated in dendritic spines. To elucidate the role of neurogranin in synaptic plasticity, we constructed a computational model with emphasis on the interaction of calmodulin with neurogranin, calcineurin, and CaMKII. The model shows how the Ca²⁺ transients that occur during LTD or LTP induction affect calmodulin and how the resulting activation of calcineurin and CaMKII affects AMPA receptor-mediated transmission. In the model, knockout of neurogranin strongly diminishes the LTP induced by a single 100 Hz, 1 s tetanus and slightly enhances LTD, in accord with experimental data. Our simulations show that exchange of calmodulin between a spine and its parent dendrite is limited. Therefore, inducing LTP with a short tetanus requires calmodulin stored in spines in the form of rapidly dissociating calmodulin–neurogranin complexes.

Key words: bidirectional plasticity; mathematical model; calmodulin; kinetics; calcium transients; AMPA receptors

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Received Feb. 17, 2006; revised June 1, 2006; accepted June 1, 2006.

Correspondence should be addressed to Dr. Anatol M. Zhabotinsky, Department of Chemistry, Brandeis University, Waltham, MA 02454-9110. Email: zhabotin{at}brandeis.edu

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