Emergence and Homeostasis of Functional Maps in Hippocampal Neurons

Abstract

Systematic investigations through several experimental techniques have revealed that hippocampal pyramidal neurons express voltage gated ion channels (VGICs) with well-defined gradients along their dendritic arbor. These actively maintained gradients in various dendritic VGICs effectuate several stereotypic, topographically continuous functional gradients along the topograph of the dendritic arbor, and have been referred to as intraneuronal functional maps. The prime goal of my thesis was to understand the emergence and homeostasis of the several coexistent functional maps that express within hippocampal pyramidal neurons. In the first part of the thesis, we focus only on spatial interactions between ion channels and analyzed the role of such interactions in the emergence of functional maps. We developed a generalized quantitative framework, the influence field, to analyze the extent of influence of a spatially localized VGIC cluster. Employing this framework, we showed that a localized VGIC cluster could have spatially widespread influence, and was heavily reliant on the specific physiological property and background conductances. Using the influence field model, we reconstructed functional gradients from VGIC conductance gradients, and demonstrated that the cumulative contribution of VGIC conductances in adjacent compartments plays a critical role in determining physiological properties at a given location. These results suggested that spatial interactions among spatially segregated VGIC clusters are necessary for the emergence of the functional maps. In the second part of the thesis, we assessed the specific roles of only kinetic interactions between ion channels in determining physiological properties by employing a single-compartmental model. In doing this, we analyzed the roles of interactions among several VGICs in regulating intrinsic response dynamics. Using global sensitivity analysis, we showed that functionally similar models could be achieved even when underlying parameters displayed tremendous variability and exhibited weak pair-wise correlations. These results suggested that that response homeostasis could be achieved through several non-unique channel combinations, as an emergent consequence of kinetic interactions among these channel conductances. In the final part of the thesis, we analyzed the combined impact of both spatial and kinetic interactions among ion channel conductances on the emergence and homeostasis of functional maps in a neuronal model endowed with extensive dendritic arborization. To do this, we performed global sensitivity analysis on morphologically realistic conductance-based models of hippocampal pyramidal neurons that coexpressed six functional maps. We found topographically continuous functional maps to emerge from disparate model parameters with weak pair-wise correlations between parameters. These results implied that individual channel properties need not be set at constant values in achieving overall homeostasis of several coexistent functional maps. We suggest collective channelostasis, where several channels regulate their properties and expression profiles in an uncorrelated manner, as an alternative for accomplishing functional map homeostasis. Finally, we developed a methodology to assess the contribution of individual channel conductances to the various functional measurements employing virtual knockout simulations. We found that the deletion of individual channels resulted in variable, measurement-and location-specific impacts across the model population.