Homeostasis of functional maps in active dendrites emerges in the absence of individual channelostasis

Abstract

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, measurementand 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. C hannel 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 l...

HCN channels enhance spike phase coherence and regulate the phase of spikes and LFPs in the theta-frequency range

“…Future studies should therefore focus on how the localization and targeting of these channel types are maintained across the somatodendritic arbor toward location-dependent regulation of LFPs, spike phases, and their coherence. In this context, it would be interesting to ask whether analogous LFPs and spike phases, and thereby analogous phase codes and cell assemblies, can be achieved with different channel/receptor combinations (58)(59)(60)63).…”

Active dendrites regulate the impact of gliotransmission on rat hippocampal pyramidal neurons

“…Computational modeling procedures were similar to procedures in ref. 26 and involved a biophysically realistic conductance-based multicompartmental model that was constructed within the NEURON simulation environment (37), using a morphological reconstruction of a CA1 pyramidal neuron (n123) taken from the Neuromorpho.org database (38,39). Passive and active (five different ion channels: Na, KDR, KA, CaT, and HCN) properties of the model neuron were set to match several somatodendritic measurements from CA1 pyramidal neurons (15-17, 26, 30, 40-42).…”

“…For instance, the spatial spread of the slower gliotransmission could be larger than that of faster neurotransmission as the cable length constant drops significantly with increase in the frequency of the input signal (22), implying a much wider reach of glial-origin signals compared with neurotransmission. Additionally, the density, voltage dependence, and activation/inactivation kinetics of channels in the dendrites confer frequency-dependent processing capabilities, thereby allowing differential processing of slow vs. fast signals (12,14,15,(23)(24)(25)(26). As several passive and active components and significant interactions among them contribute to such Significance Glial cells in the brain actively communicate with neurons through release of transmitter molecules that result in neuronal voltage deflections, thereby playing vital roles in neuronal information processing.…”

Degeneracy in hippocampal physiology and plasticity

“…http://dx.doi.org/10.1101/203943 doi: bioRxiv preprint first posted online Oct. 16, 2017; disparate measurements from the same neuron, even in a location dependent manner (Grashow et al, 2010;Rathour and Narayanan, 2014;Taylor et al, 2009). Additionally, acute blockade of one specific channel results in weakly correlated changes in different measurements in the same neuron (Rathour et al, 2016).…”

“…3.2) that employs a stochastic search algorithm spanning a large parametric space and optimizes for multiple physiological objectives (Foster et al, 1993;Goldman et al, 2001;Marder, 2011;Marder and Goaillard, 2006;Marder and Taylor, 2011;Prinz et al, 2004;Rathour and Narayanan, 2014); (b) the theoretical and experimental assessment of the links between peer-reviewed) is the author/funder. All rights reserved.…”