Modulation of GABAergic Transmission by Activity via Postsynaptic Ca2+-Dependent Regulation of KCC2 Function

Fiumelli, Hubert; Cancedda, Laura; Poo, Mu‐ming

doi:10.1016/j.neuron.2005.10.025

Cited by 196 publications

(190 citation statements)

References 38 publications

(63 reference statements)

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“…Activation of 5-HT 2A R still induced a hyperpolarizing shift of E IPSP after blocking Ca -dependent PKC abolishes the spiking-induced shift in E Cl (34). In agreement with a negative effect of intracellular Ca 2+ on KCC2 function, NMDA receptor activation leads to Ca 2+ influx that ultimately causes protein phosphatase 1-mediated dephosphorylation of KCC2 residue Ser940 and depolarizing shift of E Cl (37).…”

Section: Discussionsupporting

confidence: 57%

Activation of 5-HT2A receptors upregulates the function of the neuronal K-Cl cotransporter KCC2

Bos

Sadlaoud

Boulenguez

et al. 2012

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

154

168

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In healthy adults, activation of γ-aminobutyric acid (GABA) A and glycine receptors inhibits neurons as a result of low intracellular chloride concentration ([Cl -] i ), which is maintained by the potassium-chloride cotransporter KCC2. A reduction of KCC2 expression or function is implicated in the pathogenesis of several neurological disorders, including spasticity and chronic pain following spinal cord injury (SCI). Given the critical role of KCC2 in regulating the strength and robustness of inhibition, identifying tools that may increase KCC2 function and, hence, restore endogenous inhibition in pathological conditions is of particular importance. We show that activation of 5-hydroxytryptamine (5-HT) type 2A receptors to serotonin hyperpolarizes the reversal potential of inhibitory postsynaptic potentials (IPSPs), E IPSP , in spinal motoneurons, increases the cell membrane expression of KCC2 and both restores endogenous inhibition and reduces spasticity after SCI in rats. Up-regulation of KCC2 function by targeting 5-HT 2A receptors, therefore, has therapeutic potential in the treatment of neurological disorders involving altered chloride homeostasis. However, these receptors have been implicated in several psychiatric disorders, and their effects on pain processing are controversial, highlighting the need to further investigate the potential systemic effects of specific 5-HT 2A R agonists, such as (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine hydrobromide (TCB-2). ] i (depolarizing shift of the chloride equilibrium potential, E Cl ) dramatically compromises the inhibitory control of firing rate and excitatory inputs (5-7). Given the role of KCC2 in regulating the strength of inhibitory synaptic transmission, identifying tools that may increase KCC2 function and, hence, restore endogenous inhibition in pathological conditions is of particular importance.Spasticity is a disabling complication affecting individuals with spinal cord injury (SCI) and is characterized by a velocity-dependent increase in muscle tone resulting from hyperexcitable stretch reflexes, spasms, and hypersensitivity to normally innocuous sensory stimulations (8, 9). Down-regulation of KCC2 after SCI in rats is implicated in the development of spasticity (10) and chronic pain (11,12). Notably, the expression of KCC2 in the motoneuron membrane is reduced, and, concomitantly, the density of cytoplasmic clusters is higher, suggesting that the surface stability of the transporter is reduced in these pathological conditions (10).Mounting evidence indicates that phosphorylation of KCC2 in the C-terminal intracellular domain dynamically regulates its activity and surface expression (1). In particular, phosphorylation by protein kinase (PK)C, enhances KCC2 activity and reduces endocytosis (13). Interestingly, activation of 5-hydroxytryptamine type 2 receptors (5-HT 2 Rs) to serotonin stimulates PKC and strengthens the left-right alternation of motor bursts observed during locomotion (14-16), which rely on reciprocal inhibition (17, 18). ...

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Section: Discussionsupporting

confidence: 57%

Activation of 5-HT2A receptors upregulates the function of the neuronal K-Cl cotransporter KCC2

Bos

Sadlaoud

Boulenguez

et al. 2012

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

154

168

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“…Furthermore, relatively high concentrations of caffeine bath application (10 m m ; acting via adenosine receptors) robustly downregulated KCC2 function and depolarized E GABA (Fiumelli et al . 2005). Together these results highlight the idea that [Ca 2+ ] i elevation from intracellular stores may be a critical checkpoint that determines the direction of KCC2 regulation downstream of G q ‐GPCR signalling.…”

Section: Gpcr Modulation: a Brief Overviewmentioning

confidence: 99%

Regulation of neuronal chloride homeostasis by neuromodulators

Mahadevan

Woodin

2016

The Journal of Physiology

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KCC2 is the central regulator of neuronal Cl− homeostasis, and is critical for enabling strong hyperpolarizing synaptic inhibition in the mature brain. KCC2 hypofunction results in decreased inhibition and increased network hyperexcitability that underlies numerous disease states including epilepsy, neuropathic pain and neuropsychiatric disorders. The current holy grail of KCC2 biology is to identify how we can rescue KCC2 hypofunction in order to restore physiological levels of synaptic inhibition and neuronal network activity. It is becoming increasingly clear that diverse cellular signals regulate KCC2 surface expression and function including neurotransmitters and neuromodulators. In the present review we explore the existing evidence that G‐protein‐coupled receptor (GPCR) signalling can regulate KCC2 activity in numerous regions of the nervous system including the hypothalamus, hippocampus and spinal cord. We present key evidence from the literature suggesting that GPCR signalling is a conserved mechanism for regulating chloride homeostasis. This evidence includes: (1) the activation of group 1 metabotropic glutamate receptors and metabotropic Zn2+ receptors strengthens GABAergic inhibition in CA3 pyramidal neurons through a regulation of KCC2; (2) activation of the 5‐hydroxytryptamine type 2A serotonin receptors upregulates KCC2 cell surface expression and function, restores endogenous inhibition in motoneurons, and reduces spasticity in rats; and (3) activation of A3A‐type adenosine receptors rescues KCC2 dysfunction and reverses allodynia in a model of neuropathic pain. We propose that GPCR‐signals are novel endogenous Cl− extrusion enhancers that may regulate KCC2 function.

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“…Furthermore, the streams may partially insulate the immature projection neurons from the interneurons, and thereby reduce their exposure to GABA. Developmental modulation in the chloride reversal potential, switching the early excitatory role of GABA to its later inhibitory action, is controlled by the KCC2 potassium-chloride pump in projection neurons (Rivera et al, 1999;Fiumelli et al, 2005), and GABA itself is sufficient to drive this switch (Ganguly et al, 2001). In addition, premature expression of KCC2 accelerates onset of this switch and has significant consequences for the long-term maturation of projection neurons (Cancedda et al, 2007).…”

Section: Why Have Interneuron Migratory Streams?mentioning

confidence: 99%

Regional Distribution of Cortical Interneurons and Development of Inhibitory Tone Are Regulated by Cxcl12/Cxcr4 Signaling

Li¹,

Adesnik²,

Li³

et al. 2008

J. Neurosci.

174

222

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Interneurons are born in subcortical germinative zones and tangentially migrate in multiple streams above and below the developing cortex, and then, at the appropriate developmental stage, migrate radially into the cortex. The factors that control the formation of and the timing of exit from the streams remain obscure; moreover, the rationale for this complicated developmental plan is unclear. We show that a chemokine, Cxcl12, is an attractant for interneurons during the stage of stream formation and tangential migration. Furthermore, the timing of exit from the migratory streams accompanies loss of responsiveness to Cxcl12 as an attractant. Mice with mutations in Cxcr4 have disorganized migratory streams and deletion of Cxcr4 after the streams have formed precipitates premature entry into the cortical plate. In addition, constitutive deletion of Cxcr4 specifically in interneurons alters the regional distribution of interneurons within the cortex and leads to interneuron laminar positioning defects in the postnatal cortex. To examine the role of interneuron distribution on the development of cortical circuitry, we generated mice with focal defects in interneuron distribution and studied the density of postnatal inhibitory innervation in areas with too many and too few interneurons. Interestingly, alterations in IPSC frequency and amplitude in areas with excess interneurons tend toward normalization of inhibitory tone, but in areas with reduced interneuron density this system fails. Thus, the processes controlling interneuron sorting, migration, regional distribution, and laminar positioning can have significant consequences for the development of cortical circuitry and may have important implications for a range of neurodevelopmental disorders.

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Modulation of GABAergic Transmission by Activity via Postsynaptic Ca2+-Dependent Regulation of KCC2 Function

Cited by 196 publications

References 38 publications

Activation of 5-HT2A receptors upregulates the function of the neuronal K-Cl cotransporter KCC2

Activation of 5-HT2A receptors upregulates the function of the neuronal K-Cl cotransporter KCC2

Regulation of neuronal chloride homeostasis by neuromodulators

Regional Distribution of Cortical Interneurons and Development of Inhibitory Tone Are Regulated by Cxcl12/Cxcr4 Signaling

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