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.1245423

Cited by 185 publications

(285 citation statements)

References 43 publications

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“…Indeed, transcriptional upregulation of both kcc-2 and abts-1 during C. elegans development has been previously described (Tanis et al 2009;Bellemer et al 2011). We note, however, that a recent report suggests that Cl 2 transporters merely provide assistance to a more dominant role of local impermeant anions in setting [Cl 2 ] i (Glykys et al 2014), so other factors may also contribute to the muscimol response shift.…”

Section: Discussionmentioning

confidence: 48%

An Evolutionarily Conserved Switch in Response to GABA Affects Development and Behavior of the Locomotor Circuit of Caenorhabditis elegans

Han¹,

Bellemer

Koelle

2015

Genetics

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The neurotransmitter gamma-aminobutyric acid (GABA) is depolarizing in the developing vertebrate brain, but in older animals switches to hyperpolarizing and becomes the major inhibitory neurotransmitter in adults. We discovered a similar developmental switch in GABA response in Caenorhabditis elegans and have genetically analyzed its mechanism and function in a well-defined circuit. Worm GABA neurons innervate body wall muscles to control locomotion. Activation of GABA A receptors with their agonist muscimol in newly hatched first larval (L1) stage animals excites muscle contraction and thus is depolarizing. At the mid-L1 stage, as the GABAergic neurons rewire onto their mature muscle targets, muscimol shifts to relaxing muscles and thus has switched to hyperpolarizing. This muscimol response switch depends on chloride transporters in the muscles analogous to those that control GABA response in mammalian neurons: the chloride accumulator sodium-potassium-chloride-cotransporter-1 (NKCC-1) is required for the early depolarizing muscimol response, while the two chloride extruders potassium-chloride-cotransporter-2 (KCC-2) and anion-bicarbonate-transporter-1 (ABTS-1) are required for the later hyperpolarizing response. Using mutations that disrupt GABA signaling, we found that neural circuit development still proceeds to completion but with an 6-hr delay. Using optogenetic activation of GABAergic neurons, we found that endogenous GABA A signaling in early L1 animals, although presumably depolarizing, does not cause an excitatory response. Thus a developmental depolarizing-tohyperpolarizing shift is an ancient conserved feature of GABA signaling, but existing theories for why this shift occurs appear inadequate to explain its function upon rigorous genetic analysis of a well-defined neural circuit.

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Section: Discussionmentioning

confidence: 48%

An Evolutionarily Conserved Switch in Response to GABA Affects Development and Behavior of the Locomotor Circuit of Caenorhabditis elegans

Han¹,

Bellemer

Koelle

2015

Genetics

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“…As such, agents that potentiate KCC2 activity or prevent S940 dephosphorylation may be novel therapeutic strategies for seizure-related disorders. Finally, the role KCC2 plays in regulating neuronal Cl -homeostasis is contentious, as a recent study suggests that this parameter in adult neurons is set by impermeant anions, rather than KCC2 activity (33). However, our results suggest that under pathological conditions, KCC2 activity plays a critical role in limiting the onset and severity of SE.…”

Section: Positive Modulation Of Kcc2 Function Upon Inhibition Of Proteinmentioning

confidence: 54%

KCC2 activity is critical in limiting the onset and severity of status epilepticus

Silayeva

Deeb

Hines

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

119

137

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The K + /Cl -cotransporter (KCC2) allows adult neurons to maintain low intracellular Cl -levels, which are a prerequisite for efficient synaptic inhibition upon activation of γ-aminobutyric acid receptors. Deficits in KCC2 activity are implicated in epileptogenesis, but how increased neuronal activity leads to transporter inactivation is ill defined. In vitro, the activity of KCC2 is potentiated via phosphorylation of serine 940 (S940). Here we have examined the role this putative regulatory process plays in determining KCC2 activity during status epilepticus (SE) using knockin mice in which S940 is mutated to an alanine (S940A). In wild-type mice, SE induced by kainate resulted in dephosphorylation of S940 and KCC2 internalization. S940A homozygotes were viable and exhibited comparable basal levels of KCC2 expression and activity relative to WT mice. However, exposure of S940A mice to kainate induced lethality within 30 min of kainate injection and subsequent entrance into SE. We assessed the effect of the S940A mutation in cultured hippocampal neurons to explore the mechanisms underlying this phenotype. Under basal conditions, the mutation had no effect on neuronal Cl -extrusion. However, a selective deficit in KCC2 activity was seen in S940A neurons upon transient exposure to glutamate. Significantly, whereas the effects of glutamate on KCC2 function could be ameliorated in WT neurons with agents that enhance S940 phosphorylation, this positive modulation was lost in S940A neurons. Collectively our results suggest that phosphorylation of S940 plays a critical role in potentiating KCC2 activity to limit the development of SE.F ast synaptic inhibition in the adult brain is largely mediated via the activation of γ-aminobutyric acid receptors (GABA A Rs). The ability of neurons to maintain low intracellular Cl -is dependent upon the activity of the K + /Cl -cotransporter KCC2. KCC2 expression in the rodent brain is developmentally regulated with low levels evident before birth that then dramatically increase from postnatal day 7 (P7) onwards and correlate with the appearance of hyperpolarizing GABA A R currents (1). KCC2 null mice die shortly after birth, exhibit high levels of intracellular Cl -and anomalous excitatory actions of GABA and glycine, highlighting the vital role of KCC2 (2). In addition to regulating Cl -transport, KCC2 exhibits transporter-independent properties that affect glutamate receptors and dendritic spines (3-6).Status epilepticus (SE) is a state of continuous seizures that is highly lethal and leads to long-term neurological deficits in survivors. A key feature of SE is impaired GABAergic inhibition (7) that manifests clinically as resistance to the GABA A modulator diazepam (8). The prevailing hypothesis of impaired GABAergic signaling during SE is displacement of GABA A receptors from the synapse and a reduction in the number of receptors on the cell surface (9). However, an additional component that could contribute to the compromised inhibition during SE is a buildup of intracellular C...

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“…For instance, [Cl 2 ] i decreases from .30 mM in the immature to a 5-10 mM range in the adult (33), whereas down-regulation of the Cl 2 exporter KCC2 in various pathologic states leads to an increase of [Cl 2 ] i of .10 mM (1). [Cl 2 ] o has been shown to vary greatly as a result of pathologies such as ischemia, anoxia, and changes in the content of the extracellular matrix (46)(47)(48). For example, anoxia-related changes in [Cl 2 ] o concentration can exceed 30 mM (46).…”

Section: Discussionmentioning

confidence: 99%

“…6B, left). Moreover, [Cl 2 ] o activity-related changes are predicted to add up to longerterm alterations under pathologic states such as anoxia or ischemia (46)(47)(48). Because anoxia-related changes in [Cl 2 ] o can exceed 30 mM (46), the total change of [Cl 2 ] o during synaptic events could exceed 55 mM in the synaptic cleft in anoxic conditions.…”

Section: Vol 29 October 2015mentioning

confidence: 99%

Allosteric modulation of metabotropic glutamate receptors by chloride ions

et al. 2015

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Metabotropic glutamate receptors (mGluRs) play key roles in the modulation of many synapses. Chloride (Cl 2 ) is known to directly bind and regulate the function of different actors of neuronal activity, and several studies have pointed to the possible modulation of mGluRs by Cl 2 . Herein, we demonstrate that Cl 2 behaves as a positive allosteric modulator of mGluRs. For example, whereas glutamate potency was 3.08 6 0.33 mM on metabotropic glutamate (mGlu) 4 receptors in high-Cl 2 buffer, signaling activity was almost abolished in low Cl 2 in cell-based assays.

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Local Impermeant Anions Establish the Neuronal Chloride Concentration

Cited by 185 publications

References 43 publications

An Evolutionarily Conserved Switch in Response to GABA Affects Development and Behavior of the Locomotor Circuit of Caenorhabditis elegans

An Evolutionarily Conserved Switch in Response to GABA Affects Development and Behavior of the Locomotor Circuit of Caenorhabditis elegans

KCC2 activity is critical in limiting the onset and severity of status epilepticus

Allosteric modulation of metabotropic glutamate receptors by chloride ions

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