Dendritic spine geometry can localize GTPase signaling in neurons.
Dendritic spines are the postsynaptic terminals of most excitatory synapses in the mammalian brain. Learning and memory are associated with long-lasting structural remodeling of dendritic spines through an actin-mediated process regulated by the Rho-family GTPases RhoA, Rac, and Cdc42. These GTPases undergo sustained activation after synaptic stimulation, but whereas Rho activity can spread from the stimulated spine, Cdc42 activity remains localized to the stimulated spine. Because Cdc42 itself diffuses rapidly in and out of the spine, the basis for the retention of Cdc42 activity in the stimulated spine long after synaptic stimulation has ceased is unclear. Here we model the spread of Cdc42 activation at dendritic spines by means of reaction-diffusion equations solved on spine-like geometries. Excitable behavior arising from positive feedback in Cdc42 activation leads to spreading waves of Cdc42 activity. However, because of the very narrow neck of the dendritic spine, wave propagation is halted through a phenomenon we term geometrical wave-pinning. We show that this can account for the localization of Cdc42 activity in the stimulated spine, and, of interest, retention is enhanced by high diffusivity of Cdc42. Our findings are broadly applicable to other instances of signaling in extreme geometries, including filopodia and primary cilia.
Program in Computational Biology and Bioinformatics, Duke University Medical Center, Durham, NC 27710 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710 samurami@gmail.com.
Samuel A
SA
Ramirez
Department of Biology, University of Maryland, College Park, MD 20742.
Sridhar
S
Raghavachari
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710.
Daniel J
DJ
Lew
D000199:Actins / Q000378:metabolism; D003198:Computer Simulation; D049229:Dendritic Spines / Q000201:enzymology*; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D008959:Models, Neurological; D009474:Neurons / Q000166:cytology* / Q000201:enzymology*; D015398:Signal Transduction; D013569:Synapses / Q000201:enzymology; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
D000199:Actins; D020558:GTP Phosphohydrolases; D020764:cdc42 GTP-Binding Protein