Role of the neurogranin concentrated in spines in the induction of long-term potentiation.
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.
Zhabotinsky
Anatol M
AM
Department of Chemistry, Brandeis University, Waltham, Massachusetts 02454-9110, USA. zhabotin@brandeis.edu
Camp
R Nicholas
RN
Epstein
Irving R
IR
Lisman
John E
JE
D002118:Calcium / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology; D002147:Calmodulin / Q000502:physiology; D003198:Computer Simulation; D049229:Dendritic Spines / Q000502:physiology*; D017774:Long-Term Potentiation; D008959:Models, Neurological; D051579:Neurogranin / Q000502:physiology*; D018091:Receptors, AMPA / Q000502:physiology; D009435:Synaptic Transmission
D002147:Calmodulin; D018091:Receptors, AMPA; D051579:Neurogranin; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium