Homeostasis of functional maps in active dendrites emerges in the absence of individual channelostasis.
The maintenance of ion channel homeostasis, or channelostasis, is a complex puzzle in neurons with extensive dendritic arborization, encompassing a combinatorial diversity of proteins that encode these channels and their auxiliary subunits, their localization profiles, and associated signaling machinery. Despite this, neurons exhibit amazingly stereotypic, topographically continuous maps of several functional properties along their active dendritic arbor. Here, we asked whether the membrane composition of neurons, at the level of individual ion channels, is constrained by this structural requirement of sustaining several functional maps along the same topograph. We performed global sensitivity analysis on morphologically realistic conductance-based models of hippocampal pyramidal neurons that coexpressed six well-characterized functional maps along their trunk. We generated randomized models by varying 32 underlying parameters and constrained these models with quantitative experimental measurements from the soma and dendrites of hippocampal pyramidal neurons. Analyzing valid models that satisfied experimental constraints on all six functional maps, we found topographically analogous functional maps to emerge from disparate model parameters with weak pairwise correlations between parameters. Finally, we derived a methodology to assess the contribution of individual channel conductances to the various functional measurements, using virtual knockout simulations on the valid model population. We found that the virtual knockout of individual channels resulted in variable, measurement- and location-specific impacts across the population. Our results suggest collective channelostasis as a mechanism behind the robust emergence of analogous functional maps and have significant ramifications for the localization and targeting of ion channels and enzymes that regulate neural coding and homeostasis.
Cellular Neurophysiology Laboratory, Molecular Biophysics Unit, Indian Institute of Science, Bangalore, Karnataka 560012, India.
Rahul Kumar
RK
Rathour
Rishikesh
R
Narayanan
D056547:CA1 Region, Hippocampal / Q000378:metabolism; D003198:Computer Simulation; D003712:Dendrites / Q000378:metabolism*; D055786:Gene Knockout Techniques; D006706:Homeostasis; D015640:Ion Channel Gating; D007473:Ion Channels / Q000378:metabolism*; D008959:Models, Neurological; D017966:Pyramidal Cells / Q000378:metabolism; D015203:Reproducibility of Results
D007473:Ion Channels