physiochemical principles of ampar insertion in dendritic spines.
Name: Miriam Kathleen Bell
Grad Year: 2021
Dendritic spines are small signaling compartments in neurons and house important signaling networks, receptors, and molecules associated with learning and memory. In particular, Ca2+/calmodulin-dependent protein kinase II (CaMKII), protein phosphatase 1 (PP1), and -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) have been identified as molecular markers of memory, suggesting that their spatio-temporal dynamics play an important role in structural plasticity. Furthermore, dendritic spines have characteristic shapes that have been linked to healthy state, disease, aging, and other factors; however, the exact relationship between shape and function remains unknown. To elucidate this relationship, we developed a spatial model of Ca2+-influx through N-methyl-D-aspartate receptor (NMDAR), CaMKII/PP1 activation, and AMPAR insertion in a realistic spine geometry. Using this model, we show that i) variables in membrane voltage mediated Ca2+-influx, particularly the number of active NMDAR and extracellular Ca2+ levels, primarily regulate cytosolic protein dynamics through their impact on Ca2+ dynamics. ii) AMPAR dynamics depend on a combination of membrane curvature effects, endoplasmic reticulum (ER) spatial distribution, cytosolic protein concentrations, and stargazin binding. iii) AMPAR levels depend on both exocytosis from cytosolic stores and, more significantly, diffusion of AMPAR from extrasynaptic membrane (ESM) regions on the dendrite.
Industry Application Area(s)
Life Sciences/Medical Devices & Instruments