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Heterogeneous off-target impact of ion-channel deletion on intrinsic properties of hippocampal model neurons that self-regulate calcium

Srikanth, S and Narayanan, R (2023) Heterogeneous off-target impact of ion-channel deletion on intrinsic properties of hippocampal model neurons that self-regulate calcium. In: Frontiers in Cellular Neuroscience, 17 .

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Official URL: https://doi.org/10.3389/fncel.2023.1241450


How do neurons that implement cell-autonomous self-regulation of calcium react to knockout of individual ion-channel conductances? To address this question, we used a heterogeneous population of 78 conductance-based models of hippocampal pyramidal neurons that maintained cell-autonomous calcium homeostasis while receiving theta-frequency inputs. At calcium steady-state, we individually deleted each of the 11 active ion-channel conductances from each model. We measured the acute impact of deleting each conductance (one at a time) by comparing intrinsic electrophysiological properties before and immediately after channel deletion. The acute impact of deleting individual conductances on physiological properties (including calcium homeostasis) was heterogeneous, depending on the property, the specific model, and the deleted channel. The underlying many-to-many mapping between ion channels and properties pointed to ion-channel degeneracy. Next, we allowed the other conductances (barring the deleted conductance) to evolve towards achieving calcium homeostasis during theta-frequency activity. When calcium homeostasis was perturbed by ion-channel deletion, post-knockout plasticity in other conductances ensured resilience of calcium homeostasis to ion-channel deletion. These results demonstrate degeneracy in calcium homeostasis, as calcium homeostasis in knockout models was implemented in the absence of a channel that was earlier involved in the homeostatic process. Importantly, in reacquiring homeostasis, ion-channel conductances and physiological properties underwent heterogenous plasticity (dependent on the model, the property, and the deleted channel), even introducing changes in properties that were not directly connected to the deleted channel. Together, post-knockout plasticity geared towards maintaining homeostasis introduced heterogenous off-target effects on several channels and properties, suggesting that extreme caution be exercised in interpreting experimental outcomes involving channel knockouts. Copyright © 2023 Srikanth and Narayanan.

Item Type: Journal Article
Publication: Frontiers in Cellular Neuroscience
Publisher: Frontiers Media SA
Additional Information: The copyright for this article belongs to Author.
Keywords: calcium; ion channel; messenger RNA; n methyl dextro aspartic acid receptor, action potential; Article; artificial neural network; autoregulation; calcium homeostasis; electrophysiology; functional magnetic resonance imaging; gene deletion; gene expression; hippocampus; human; human cell; intrinsic activity; knockout gene; mathematical model; nerve cell plasticity; neurophysiology; oscillation; pleiotropy; pyramidal nerve cell; steady state; stochastic model; synapse
Department/Centre: Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited: 04 Mar 2024 09:46
Last Modified: 04 Mar 2024 09:46
URI: https://eprints.iisc.ac.in/id/eprint/84394

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