Response to Comments on “Local impermeant anions establish the neuronal chloride concentration”

Glykys, Joseph; Dzhala, Volodymyr; Egawa, Kiyoshi; Balena, Trevor; Saponjian, Yero; Kuchibhotla, Kishore V.; Bacskai, Brian J.; Kahle, Kristopher T.; Zeuthen, Thomas; Staley, Kevin J.

doi:10.1126/science.1253146

Cited by 16 publications

(12 citation statements)

References 24 publications

(24 reference statements)

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“…No energy is required to maintain local differences in [Cl − ] i that arise due to local differences in immobile anions concentrations. The intra- and extracellular Cl − microdomains along a dendrite are not evidence of “an eternal motion machine” [63,64]. For example in Figure 2, diffusion of cytoplasmic Cl − from the area of high concentration to the area of low concentration is held in check by the charge separation that would be induced by Cl − diffusion, rather than the activity of the local CCCs [48].…”

Section: Cl−: the Neuronal “Packing Peanut”mentioning

confidence: 99%

Chloride Dysregulation, Seizures, and Cerebral Edema: A Relationship with Therapeutic Potential

Glykys

Dzhala

Egawa

et al. 2017

Trends in Neurosciences

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Pharmaco-resistant seizures and cytotoxic cerebral edema are serious complications of ischemic and traumatic brain injury. Intraneuronal Cl− concentration ([Cl−]i) regulation impacts both cell volume homeostasis and Cl− permeable GABAA receptor-dependent membrane excitability. Understanding the pleiotropic molecular determinants of neuronal [Cl−]i –cytoplasmic impermeant anions, polyanionic extracellular matrix (ECM) glycoproteins, and plasmalemmal Cl− transporters– could help identify novel anti-convulsive and neuroprotective targets. The cation-Cl− cotransporters and ECM metalloproteinases may be particularly druggable targets for intervention. Here, we establish a paradigm that accounts for recent data regarding the complex regulatory mechanisms of neuronal [Cl−]i and how these mechanisms impact neuronal volume and excitability. We propose approaches to modulate [Cl−]i that are relevant for two common clinical sequela of brain injury: edema and seizures.

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Section: Cl−: the Neuronal “Packing Peanut”mentioning

confidence: 99%

Chloride Dysregulation, Seizures, and Cerebral Edema: A Relationship with Therapeutic Potential

Glykys

Dzhala

Egawa

et al. 2017

Trends in Neurosciences

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“…The authors argue that the CSPG ECM surrounding neurons is rich in impermeable, stationary sulfate anions that reduce the concentration of free, membrane permeant Cl − (refs. 56,57). Following digestion, the impermeant anions are replaced by permeant Cl − , shifting the equilibrium conditions for the cation chloride transport toward higher intracellular Cl − , which results in increased excitability.…”

Section: Gliosis Gliotransmission and The Composition Of The Ecmmentioning

confidence: 99%

“…Following digestion, the impermeant anions are replaced by permeant Cl − , shifting the equilibrium conditions for the cation chloride transport toward higher intracellular Cl − , which results in increased excitability. This study elicited a heated debate 57–59 , as it questions the relevance of the chloride transporters NKCC1 and KCC2 for maintenance of intracellular chloride concentrations.…”

Section: Gliosis Gliotransmission and The Composition Of The Ecmmentioning

confidence: 99%

Glia as drivers of abnormal neuronal activity

2015

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Reactive astrocytes have been proposed to become incompetent bystanders in epilepsy as a result of cellular changes rendering them unable to perform important housekeeping functions. Indeed, successful surgical treatment of mesiotemporal lobe epilepsy hinges on the removal of the glial scar. New research now extends the role of astrocytes, suggesting that they may drive the disease process by impairing the inhibitory action of neuronal GABA receptors. Here we discuss studies that include hyperexcitability resulting from impaired supply of astrocytic glutamine for neuronal GABA synthesis, and epilepsy resulting from genetically induced astrogliosis or malignant transformation, both of which render the inhibitory neurotransmitter GABA excitatory. In these examples, glial cells alter the expression or function of neuronal proteins involved in excitability. Although epilepsy has traditionally been thought of as a disease caused by changes in neuronal properties exclusively, these new findings challenge us to consider the contribution of glial cells as drivers of epileptogenesis in acquired epilepsies.

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“…In their response 297 they now suggest that DF GABA is due to Donnan-equilibration of Cl − plus an energy-requiring V m shift. If so, Cl − leaks would dissipate DF GABA , thereby necessitating never-ending V m shifts.…”

mentioning

confidence: 99%

Cation-chloride cotransporters in neuronal development, plasticity and disease

et al. 2014

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Electrical activity in neurons requires a seamless functional coupling between plasmalemmal ion channels and ion transporters. Although ion channels have been studied intensively for several decades, research on ion transporters is in its infancy. In recent years, it has become evident that one family of ion transporters, cation-chloride cotransporters (CCCs), and in particular K+–Cl− cotransporter 2 (KCC2), have seminal roles in shaping GABAergic signalling and neuronal connectivity. Studying the functions of these transporters may lead to major paradigm shifts in our understanding of the mechanisms underlying brain development and plasticity in health and disease.

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Response to Comments on “Local impermeant anions establish the neuronal chloride concentration”

Abstract: We appreciate the interest in our paper and the opportunity to clarify theoretical and technical aspects describing the influence of Donnan equilibria on neuronal chloride ion (Cl – ) distributions.

Cited by 16 publications

References 24 publications

Chloride Dysregulation, Seizures, and Cerebral Edema: A Relationship with Therapeutic Potential

Chloride Dysregulation, Seizures, and Cerebral Edema: A Relationship with Therapeutic Potential

Glia as drivers of abnormal neuronal activity

Cation-chloride cotransporters in neuronal development, plasticity and disease

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