Toward a Biophysical Model of Spike-Time Dependent Plasticity

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Presentation transcript:

Toward a Biophysical Model of Spike-Time Dependent Plasticity A Monte Carlo model of Ca2+ dynamics in dendritic spines. Kevin Franks The Salk Institute

Biochemistry of LTP/LTD? High Ca2+ through NMDARs induces LTP via CaMKII Low Ca2+ through NMDARs induces LTD via calcineurin Role for VDCCs in LTD, maybe for LTP?

About MCell Allows: Monte Carlo simulator of microphysiology 3D random walk diffusion Stochastic biochemical kinetic state transitions 3D representation of surfaces of arbitrary complexity

Spine Model

Ca2+ Sources NMDARs ~20 NMDARs at synapse VDCCs ~20 NMDARs at synapse ~ 5 VDCCs anywhere on the spine surface

Voltage-gating in MCell

Ca2+ Sinks Low density of surface pumps High density of ER pumps Spine apparatus Pumps Low density of surface pumps High density of ER pumps

Ca2+ Buffers ~100 mM Ca2+-binding proteins throughout the spine ~ 20 mM CaM at PSD s  20 optional addition of fluorescent indicators CBPs

Simulating fluorescent Ca2+ transients

Sub- & superlinear Ca2+ fluorescence Action potential EPSP Action potential + EPSP (linear sum) EPSP + Action potential (linear sum) Action potential  EPSP (50 ms apart) EPSP  Action potential (50 ms apart) See Koester & Sakmann (1998) What about [Ca2+]i?

DF/F  [Ca2+]i

An intuitive model (?)

LTP-inducing protocol EPSP 10 ms before AP

LTD-inducing protocol EPSP 10 ms after AP

Biochemistry of LTP/LTD?  High Ca2+ through NMDARs can induce LTP via CaMKII Low Ca2+ through NMDARs can induce LTD via calcineurin 

Ineffectual protocol EPSP 90 ms before AP

Problems with the simple model:

Dendritic Spines A Biochemist’s View From: Sheng and Lee Nature Neurosci, 2000

APs don’t induce Ca2+ gradients in spines...

…but EPSPs do induce Ca2+ gradients

Differential distribution of CaM

Conclusions We are able to accurately model intracellular Ca2+ dynamics at high spatial and temporal resolution. Large and moderate Ca2+ currents are not sufficient to explain the selective induction of LTP and LTD, respectively, with STDP. We suggest that differential induction decisions are made in highly organized subdomains of the spine.

Acknowledgements Thanks to: Terrence Sejnowski Thomas Bartol

Ca2+/Calmodulin Complex Calmodulin is a molecular differentiator: Responds to rapid increases in [Ca2+] Ca2+ Ca2+ Ca2+ Ca2+ 6x106 9.5x106 8x106 4.3x107 B0 B1 B2 B3 B4* 40 40 600 600 (Stable) (Unstable) (Stable)

Courtesy of Richard Weinberg

Fluorescent Ca2+ transients allow determination of endogenous buffering capacity Ks  20 means 1/20 of the Ca2+ ions remain free, or, 95% of Ca2+ entering the spine is buffered [sensor] KD B = ([Ca2+]rest + KD)([Ca2+]peak+KD)