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.Channel homeostasis, or channelostasis, refers to the regulation of the density, kinetics, voltage dependence, binding interactions, and the subcellular localization of individual ion channel types within a given cell [compared to proteostasis (1)]. Hippocampal CA1 pyramidal neurons are endowed with complex dendritic morphology and express numerous voltage-gated ion channels (VGICs), which govern critical neuronal functions across their somatodendritic arbor (2–6). Channelostasis in such neurons is an exceptionally complex puzzle, given the enormous morphological and molecular complexities accompanied by a myriad of subcellular channel localization profiles, resulting in an immense combinatorial diversity in channel expression profiles (4, 7–11). A further conundrum that compounds this complex puzzle is that neurons, despite these underlying complexities, exhibit amazingly regular gradients in several functional properties that manifest as maps along a continuous neuronal topograph (3). The coexistence of all these topographically continuous maps along the same neuronal topograph is mediated by intricately regulated subcellular localization of various VGICs.In this study, we asked whether the topographically connected structure of a complex dendritic arbor, constrained to sustain these continuous functional maps, imposes rules on the individual and collective channelostasis of underlying ion channels. Specifically, the sustenance of the coexistent functional maps has to account for observations that several VGICs govern and modulate any given functional property within a single neuron (12–15) and that there are spatially widespread, distance-dependent influences of ionic conductances across the dendritic arbor (16, 17). Do these requirements impose constraints on the expression profiles and properties of somatodendritic ion channels, if several functional maps were to be coexistent and continuous on the same neuronal topograph? Do spatial and kinetic interactions among channel gradients across the neuronal topograph facilitate or hamper robustness of the several functional maps? Does the connected dendritic structure impose strong pairwise correlations on the expression profiles of different channels that mediate the coexistence of these functional maps? What are the location-dependent contributions of different channels to the several functional maps expressed by hippocampal neurons?We addressed these questions by using the powerful global sensitivity analysis methodology on morphologically realistic neuronal models and dissected six functional maps with reference to 32 passive and active parameters that governed the neuron’s somatodendritic properties. We used detailed quantitative experimental measurements of channel distributions and of physiological properties from the soma and dendrites of CA1 pyramidal neurons to resolve the validity of 20,420 models generated by randomly assigning values for these 32 parameters. We found that disparate model parameters resulted in topographically analogous populations of these valid neuronal models with weak pairwise correlations between parameters, implying collective, and not individual/pairwise channelostasis as a mechanism behind homeostasis in functional maps. Finally, we derived a methodology, within the global sensitivity analysis framework, to assess the relative contribution of the different channel conductances to the various functional measurements, using virtual knockout simulations on the valid model population. Results from our study suggest that neural mechanisms involved in regulating functional homeostasis of topographically continuous maps need not maintain the density and properties of individual channels at fixed values at specific locations.