Neurologic complications of genetic channelopathies

Franklin, Wayne H.; Laubham, Matthew

doi:10.1016/b978-0-12-819814-8.00014-7

Cited by 4 publications

(2 citation statements)

References 23 publications

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“…Therefore, they are amenable to addressing focused questions about how pathological conditions that alter specific molecules (ion channels, receptors) confined to certain neuronal subtypes affect continuous attractor networks and associated behavioral outcomes. As synaptopathies and channelopathies are strongly associated with several neurological disorders (Kullmann, 2002; Terzic and Perez-Terzic, 2010; Grant, 2012; Poolos and Johnston, 2012; Lerche et al, 2013; Brager and Johnston, 2014; Mandolesi et al, 2015; Rivolta et al, 2020; Deng and Klyachko, 2021; Franklin and Laubham, 2021; Kessi et al, 2021; Mantegazza et al, 2021), this ability to assess the heterogeneous impact of altering specific components is invaluable from a theoretical perspective as well as from the perspective of designing specific experiments or drug targets. The process outlined here to generate heterogeneous networks could also be employed to build heterogeneous neurons and networks that mimic the several differences that are observed under specific pathological conditions.…”

Section: Discussionmentioning

confidence: 99%

HCN channels enhance robustness of patterned activity propagation in heterogeneous conductance-based ring networks

Mittal,

Narayanan

2023

Preprint

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Continuous attractor network (CAN) models lend a powerful framework that has provided deep insights about several aspects of brain physiology. However, most CAN models employ homogeneous, rate-based or artificially spiking neurons with precisely structured synaptic connectivity, precluding detailed analyses of the impact of specific neural-circuit components and associated heterogeneities on CAN dynamics. To address this caveat, we built populations of tunable and scalable conductance-based, physiologically constrained, ring network models consisting of distinct rings of excitatory and inhibitory neurons. We assessed the network for its ability to sustain robust propagation of patterned activity across the rings. First, in homogeneous ring networks, we found that robust activity propagation could be sustained through several different combinations of synaptic weights, demonstrating synaptic degeneracy in the emergence of robust activity propagation. We incorporated intrinsic heterogeneity through randomized perturbations to ion channel parameters of all neurons and synaptic heterogeneity by adding jitter to the Mexican-hat connectivity between inhibitory neurons. We found the number of networks exhibiting robust propagation of patterned activity to reduce with increase in the degree of synaptic or intrinsic heterogeneities. Motivated by the ability of intrinsic neuronal resonance to stabilize heterogeneous rate-based CAN models, we hypothesized that increasing HCN-channel (a resonating conductance) density would stabilize activity propagation in heterogeneous ring networks. Strikingly, we observed that increases in HCN-channel density resulted in a pronounced increase in the proportion of heterogeneous networks that exhibited robust activity propagation, across multiple trials and across three degrees of either form of heterogeneity. Together, heterogeneous networks made of neurons with disparate intrinsic properties and variable HCN channel densities yielded robust activity propagation, demonstrating intrinsic degeneracy in the emergence of robust activity propagation. Finally, as HCN channels also contribute to changes in excitability, we performed excitability-matched controls with fast HCN channels that do not introduce resonance. We found that fast HCN channels did not stabilize heterogeneous network dynamics over a wide range of conductance values, suggesting that the slow negative feedback loop introduced by HCN channels is a critical requirement for network stabilization. Together, our results unveil a cascade of degeneracy in ring-network physiology, spanning the molecular-cellular-network scales. These results also demonstrate a critical role for the widely expressed HCN channels in enhancing the robustness of heterogeneous neural circuits by implementing a slow negative feedback loop at the cellular scale.

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Section: Discussionmentioning

confidence: 99%

HCN channels enhance robustness of patterned activity propagation in heterogeneous conductance-based ring networks

Mittal,

Narayanan

2023

Preprint

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“…Finally, there are reports of changes to ion-channel properties and intrinsic properties spanning different neuronal subtypes under several pathophysiological and altered behavioral conditions (Kullmann and Waxman, 2010; Terzic and Perez-Terzic, 2010; Cannon, 2021; Deng and Klyachko, 2021; Franklin and Laubham, 2021; Gripp et al, 2021; Kessi et al, 2021; Mantegazza et al, 2021). Thus, future studies should explore the impact of altered channel properties/densities under different behavioral and pathological conditions on specific ion channels and the physiology of SCN neurons, as well as the impact on transitions and plasticity manifolds associated with them.…”

Section: Discussionmentioning

confidence: 99%

Plasticity manifolds and ion-channel degeneracy govern circadian oscillations of neuronal intrinsic properties in the suprachiasmatic nucleus

Nagaraj

Narayanan

2022

Preprint

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Motivation and methods: The suprachiasmatic nucleus (SCN) is the master circadian clock of the mammalian brain that sustains a neural code for circadian time through oscillations in the firing rate of constituent neurons. These cell-autonomous oscillations in intrinsic properties are mediated by plasticity in a subset of ion-channels expressed in SCN neurons and are maintained despite widespread neuron-to-neuron variability in ion channel expression profiles. How do SCN neurons undergo stable transitions and maintain precision in intrinsic properties spanning the day-night cycle if several ion channels change concomitantly in a heterogeneous neuronal population? Here, we address this important question using unbiased stochastic searches on the parametric and the plasticity spaces using populations of SCN models, each explored for multiple valid transitions spanning one complete circadian cycle (day-to-night followed by night-to-day transitions). Results: Our analyses provided three fundamental insights about the impact of heterogeneities on the circadian oscillations of SCN intrinsic properties. First, SCN neurons could achieve signature electrophysiological characteristics (day-like or night-like) despite pronounced heterogeneity in ion channel conductances, with weak pairwise correlations between their conductance values. This ion-channel degeneracy precluded the need to maintain precise ion-channel expression profiles for achieving characteristic electrophysiological signatures of SCN neurons, thus allowing for parametric heterogeneities despite functional precision. Second, it was not essential that specific conductances had to change by precise values for obtaining valid day-to-night or night-to-day transitions. This plasticity degeneracy, the ability of disparate combinations of ion-channel plasticity to yield the same functional transition, confers flexibility on individual neurons to take one of several routes to achieve valid transitions. Finally, we performed nonlinear dimensionality reduction analyses on the valid plasticity spaces and found the manifestation of a low-dimensional plasticity manifold in day-to-night transitions, but not in night-to-day transitions. These observations demonstrated that the concomitant changes in multiple ion channels are not arbitrary, but follow a structured plasticity manifold that provides a substrate for stability in achieving stable circadian oscillations. Implications: Our analyses unveil an elegant substrate, involving a synthesis of the degeneracy and the plasticity manifold frameworks, to effectuate stable circadian oscillations in a heterogeneous population of SCN neurons. Within this framework, the ability of multiple ion channels to change concomitantly provides robustness and flexibility to effectively achieve precise transitions despite widespread heterogeneities in ion-channel expression and plasticity.

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