Conjunctive changes in multiple ion channels mediate activity-dependent intrinsic plasticity in hippocampal granule cells

Mishra, Poonam; Narayanan, Rishikesh

doi:10.1016/j.isci.2022.103922

Cited by 14 publications

(9 citation statements)

References 102 publications

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“…Such insights about individual neuronal physiology and their composition could then be used to assess network scale functions such as different forms of decorrelation (Leutgeb et al, 2007; McHugh et al, 2007; Bakker et al, 2008; Clelland et al, 2009; Deng et al, 2010; Wick et al, 2010; Sahay et al, 2011; Schmidt et al, 2012; Vivar et al, 2012; Moreno-Bote et al, 2014; Wu et al, 2015; Cayco-Gajic et al, 2017; Chavlis et al, 2017; Mishra and Narayanan, 2019; 2021b; c) and engram cell formation (Liu et al, 2012; Ramirez et al, 2013; Redondo et al, 2014; Ramirez et al, 2015; Park et al, 2016; Roy et al, 2016; Titley et al, 2017; Lisman et al, 2018; Mishra and Narayanan, 2021d; 2022; Shridhar et al, 2022) assessed with morphologically realistic heterogeneous model populations of different neuronal subtypes in the hippocampus. The use of heterogeneous morphologically realistic models for all neuronal subtypes would provide deeper insights about degeneracy in the emergence of DG network function (Mishra and Narayanan, 2019; 2021c) and the role of active dendrites in mediating decorrelation as well as engram cell formation (Govindarajan et al, 2011; Chavlis et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Ion-channel degeneracy and heterogeneities in the emergence of signature physiological characteristics of dentate gyrus granule cells

Kumari,

Narayanan

2024

Preprint

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Complex systems are neither fully determined nor completely random. Biological complex systems, including single neurons, manifest intermediate regimes of randomness that recruit integration of specific combinations of functionally segregated subsystems. Such emergence of biological function provides the substrate for the expression of degeneracy, the ability of disparate combinations of subsystems to yield similar function. Here, we present evidence for the expression of degeneracy in morphologically realistic models of dentate gyrus granule cells (GC) through functional integration of disparate ion-channel combinations. We performed a 45-parameter randomized search spanning 16 active and passive ion channels, each biophysically constrained by their gating kinetics and localization profiles, to search for valid GC models. Valid models were those that satisfied 17 sub- and supra-threshold cellular-scale electrophysiological measurements from rat GCs. A vast majority (>99%) of the 15,000 random models were not electrophysiologically valid, demonstrating that arbitrarily random ion-channel combinations wouldn't yield GC functions. The 141 valid models (0.94% of 15,000) manifested heterogeneities in and cross-dependencies across local and propagating electrophysiological measurements, which matched with their respective biological counterparts. Importantly, these valid models were widespread throughout the parametric space and manifested weak cross-dependencies across different parameters. These observations together showed that GC physiology could neither be obtained by entirely random ion-channel combinations nor is there an entirely determined single parametric combination that satisfied all constraints. The complexity, the heterogeneities in measurement and parametric spaces, and degeneracy associated with GC physiology should be rigorously accounted for, while assessing GCs and their robustness under physiological and pathological conditions.

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Section: Discussionmentioning

confidence: 99%

Ion-channel degeneracy and heterogeneities in the emergence of signature physiological characteristics of dentate gyrus granule cells

Kumari,

Narayanan

2024

Preprint

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“…Although the ability of HCN channels to regulate neuronal excitability and act as pacemaking channels have been studied extensively, this stabilizing role of HCN emanating from suppression of low-frequency signals and noise has not received commensurate attention. The relevance of somato-dendritic (Magee, 1998; Williams and Stuart, 2000; Lorincz et al, 2002) and dorso-ventral (Giocomo et al, 2007; Garden et al, 2008; Malik et al, 2016) gradients in HCN- channel expression as well as neuromodulation (Robinson and Siegelbaum, 2003; Biel et al, 2009) and activity-dependent plasticity (Fan et al, 2005; Brager and Johnston, 2007; Narayanan and Johnston, 2007, 2008; Mishra and Narayanan, 2022) in these channels to such stabilizing and low-frequency noise suppression should be systematically assessed (Mittal and Narayanan, 2021).…”

Section: Discussionmentioning

confidence: 99%

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

Mittal,

Narayanan

2023

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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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“…Furthermore, plasticity in the DG GCs is known to span synaptic and intrinsic properties (Bliss & Lomo, 1973; Lopez‐Rojas et al, 2016; Mishra & Narayanan, 2021c, 2022). These observations necessitate future studies to assess the impact of neural heterogeneities on conjunctive intrinsic and synaptic plasticity, especially with reference to plasticity heterogeneities, resource allocation, and engram formation (Josselyn & Frankland, 2018; Josselyn & Tonegawa, 2020; Lisman et al, 2018; Mishra & Narayanan, 2021c; Park et al, 2016; Rao‐Ruiz et al, 2019; Silva et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Dominant role of adult neurogenesis‐induced structural heterogeneities in driving plasticity heterogeneity in dentate gyrus granule cells

2022

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Neurons and synapses manifest pronounced variability in the amount of plasticity induced by identical activity patterns. The mechanisms underlying such plasticity heterogeneity, which have been implicated in context-specific resource allocation during encoding, have remained unexplored. Here, we employed a systematic physiologically constrained parametric search to identify the cellular mechanisms behind plasticity heterogeneity in dentate gyrus granule cells. We used heterogeneous model populations to ensure that our conclusions were not biased by parametric choices in a single hand-tuned model. We found that each of intrinsic, synaptic, and structural heterogeneities independently yielded heterogeneities in synaptic plasticity profiles obtained with two different induction protocols. However, among the disparate forms of neural-circuit heterogeneities, our analyses demonstrated the dominance of neurogenesis-induced structural heterogeneities in driving plasticity heterogeneity in granule cells. We found that strong relationships between neuronal intrinsic excitability and plasticity emerged only when adult neurogenesis-induced heterogeneities in neural structure were accounted for. Importantly, our analyses showed that it was not imperative that the manifestation of neural-circuit heterogeneities must translate to heterogeneities in plasticity profiles. Specifically, despite the expression of heterogeneities in structural, synaptic, and intrinsic neuronal properties, similar plasticity profiles were attainable across all models through synergistic interactions among these heterogeneities. We assessed the parametric combinations required for the manifestation of such degeneracy in the expression of plasticity profiles. We found that immature cells showed physiological plasticity profiles despite receiving afferent inputs with weak synaptic strengths. Thus, the high intrinsic excitability of immature granule cells was sufficient to counterbalance their low excitatory drive in the expression of plasticity profile degeneracy. Together, our analyses demonstrate that disparate forms of neural-circuit heterogeneities could mechanistically drive plasticity heterogeneity, but also caution against treating neural-circuit heterogeneities as proxies for plasticity heterogeneity. Our study emphasizes the need for quantitatively characterizing the relationship between neural-circuit and plasticity heterogeneities across brain regions.Sameera Shridhar and Poonam Mishra contributed equally to this study.

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Conjunctive changes in multiple ion channels mediate activity-dependent intrinsic plasticity in hippocampal granule cells

Cited by 14 publications

References 102 publications

Ion-channel degeneracy and heterogeneities in the emergence of signature physiological characteristics of dentate gyrus granule cells

Ion-channel degeneracy and heterogeneities in the emergence of signature physiological characteristics of dentate gyrus granule cells

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

Dominant role of adult neurogenesis‐induced structural heterogeneities in driving plasticity heterogeneity in dentate gyrus granule cells

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