ArticlePLoS computational biology2011
Efficacy of synaptic inhibition depends on multiple, dynamically interacting mechanisms implicated in chloride homeostasis.
Article in PLoS computational biology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 82 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
82 citing papers in PubMed, 156 citations in OpenAlex.
- Spatiotemporal Dynamics of Lateral NaThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- Spatio-temporal dynamics of lateral NabioRxiv : the preprint server for biology · 2025Article
- Restoring Compromised ClThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Optogenetic Determination of Dynamic and Cell-Type-Specific Inhibitory Reversal Potentials.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Constitutive KCC2 Cell- and Synapse-Specifically Regulates NMDA Receptor Activity in the Spinal Cord.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Correlations of receptor desensitization of gain-of-function GABRB3 variants with clinical severity.Brain : a journal of neurology · 2024Article
- Restoring neuronal chloride extrusion reverses cognitive decline linked to Alzheimer's disease mutations.Brain : a journal of neurology · 2023Article
- Article
- Clarifying the composition of the ATP consumption factors required for maintaining ion homeostasis in mouse rod photoreceptors.Scientific reports · 2023Article
- Computational models reveal how chloride dynamics determine the optimal distribution of inhibitory synapses to minimise dendritic excitability.PLoS computational biology · 2022Article
- Focal seizures are organized by feedback between neural activity and ion concentration changes.eLife · 2022Article
- Non-monotonic effects of GABAergic synaptic inputs on neuronal firing.PLoS computational biology · 2022Article
- A Female-Specific Role for Calcitonin Gene-Related Peptide (CGRP) in Rodent Pain Models.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2022Article
- The serotonin 2A receptor agonist TCB-2 attenuates heavy alcohol drinking and alcohol-induced midbrain inhibitory plasticity.Addiction biology · 2022Article
- Ictal wavefront propagation in slices and simulations with conductance-based refractory density model.PLoS computational biology · 2022Article
- Article
- Interactions among diameter, myelination, and the Na/K pump affect axonal resilience to high-frequency spiking.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Coincident glutamatergic depolarizations enhance GABAA receptor-dependent Cl- influx in mature and suppress Cl- efflux in immature neurons.PLoS computational biology · 2021Article
- Striatal Chloride Dysregulation and Impaired GABAergic Signaling Due to Cation-Chloride Cotransporter Dysfunction in Huntington's Disease.Frontiers in cellular neuroscience · 2021Review
- Gabaergic Interneurons in Early Brain Development: Conducting and Orchestrated by Cortical Network Activity.Frontiers in molecular neuroscience · 2021Article
22 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Chloride homeostasis is a critical determinant of the strength and robustness of inhibition mediated by GABA(A) receptors (GABA(A)Rs). The impact of changes in steady state Cl(-) gradient is relatively straightforward to understand, but how dynamic interplay between Cl(-) influx, diffusion, extrusion and interaction with other ion species affects synaptic signaling remains uncertain. Here we used electrodiffusion modeling to investigate the nonlinear interactions between these processes. Results demonstrate that diffusion is crucial for redistributing intracellular Cl(-) load on a fast time scale, whereas Cl(-)extrusion controls steady state levels. Interaction between diffusion and extrusion can result in a somato-dendritic Cl(-) gradient even when KCC2 is distributed uniformly across the cell. Reducing KCC2 activity led to decreased efficacy of GABA(A)R-mediated inhibition, but increasing GABA(A)R input failed to fully compensate for this form of disinhibition because of activity-dependent accumulation of Cl(-). Furthermore, if spiking persisted despite the presence of GABA(A)R input, Cl(-) accumulation became accelerated because of the large Cl(-) driving force that occurs during spikes. The resulting positive feedback loop caused catastrophic failure of inhibition. Simulations also revealed other feedback loops, such as competition between Cl(-) and pH regulation. Several model predictions were tested and confirmed by [Cl(-)](i) imaging experiments. Our study has thus uncovered how Cl(-) regulation depends on a multiplicity of dynamically interacting mechanisms. Furthermore, the model revealed that enhancing KCC2 activity beyond normal levels did not negatively impact firing frequency or cause overt extracellular K(-) accumulation, demonstrating that enhancing KCC2 activity is a valid strategy for therapeutic intervention.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.