title: Modeling and analysis of calcium signaling events leading to long-term depression in cerebellar Purkinje cells.
abstract: Modeling and simulation of the calcium signaling events that precede long-term depression of synaptic activity in cerebellar Purkinje cells are performed using the Virtual Cell biological modeling framework. It is found that the unusually high density and low sensitivity of inositol-1,4,5-trisphosphate receptors (IP3R) are critical to the ability of the cell to generate and localize a calcium spike in a single dendritic spine. The results also demonstrate the model's capability to simulate the supralinear calcium spike observed experimentally during coincident activation of the parallel and climbing fibers. The sensitivity of the calcium spikes to certain biological and geometrical effects is investigated as well as the mechanisms that underlie the cell's ability to generate the supralinear spike. The sensitivity of calcium release rates from the IP3R to calcium concentrations, as well as IP3 concentrations, allows the calcium spike to form. The diffusion barrier caused by the small radius of the spine neck is shown to be important, as a threshold radius is observed above which a spike cannot be formed. Additionally, the calcium buffer capacity and diffusion rates from the spine are found to be important parameters in shaping the calcium spike.
authors.affiliation: Center for Cell Analysis and Modeling, University of Connecticut Health Center, Farmington, Connecticut.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Hernjak
authors.forename: Boris M
authors.initials: BM
authors.lastname: Slepchenko
authors.forename: Kathleen
authors.initials: K
authors.lastname: Fernald
authors.forename: Charles C
authors.initials: CC
authors.lastname: Fink
authors.forename: Dale
authors.initials: D
authors.lastname: Fortin
authors.forename: Ion I
authors.initials: II
authors.lastname: Moraru
authors.forename: James
authors.initials: J
authors.lastname: Watras
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Loew
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology*; D002462:Cell Membrane / Q000502:physiology; D002531:Cerebellum / Q000502:physiology; D003198:Computer Simulation; D004721:Endoplasmic Reticulum / Q000502:physiology; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors; D015640:Ion Channel Gating / Q000502:physiology; D036881:Long-Term Synaptic Depression / Q000502:physiology*; D008959:Models, Neurological; D011689:Purkinje Cells / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D015220:Calcium Channels; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D002118:Calcium