Serotoninergic Modulation of Chloride Homeostasis during Maturation of the Locomotor Network in Zebrafish

Brustein, Edna; Drapeau, Pierre

doi:10.1523/jneurosci.2017-05.2005

Cited by 42 publications

(42 citation statements)

References 41 publications

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“…In neurons from control embryos (n ϭ 4) and embryos expressing KCC2-C568A (n ϭ 3), SBs were always depolarizing from rest (Fig. 2C, black and blue traces at resting potential expanded in Ci) as would be expected for neurons with a high intracellular chloride content (Saint-Amant and Drapeau, 2000;Brustein and Drapeau, 2005). In contrast, among the spontaneously active neurons from embryos expressing KCC2 (n ϭ 5), SBs were either not obvious at rest or were hyperpolarizing from rest (Fig.…”

Section: Kcc2 Overexpression Reverses the Chloride Gradientmentioning

confidence: 54%

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Neurogenic Role of the Depolarizing Chloride Gradient Revealed by Global Overexpression of KCC2 from the Onset of Development

Reynolds¹,

Brustein²,

Liao³

et al. 2008

J. Neurosci.

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GABA-and glycine-induced depolarization is thought to provide important developmental signals, but the role of the underlying chloride gradient has not been examined from the onset of development. We therefore overexpressed globally the potassium-chloride cotransporter 2 (KCC2) in newly fertilized zebrafish embryos to reverse the chloride gradient. This rendered glycine hyperpolarizing in all neurons, tested at the time that motor behaviors (but not native KCC2) first appear. KCC2 overexpression resulted in fewer mature spontaneously active spinal neurons, more immature silent neurons, and disrupted motor activity. We observed fewer motoneurons and interneurons, a reduction in the elaboration of axonal tracts, and smaller brains and spinal cords. However, we observed no increased apoptosis and a normal complement of sensory neurons, glia, and progenitors. These results suggest that chloride-mediated excitation plays a crucial role in promoting neurogenesis from the earliest stages of embryonic development.

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Section: Kcc2 Overexpression Reverses the Chloride Gradientmentioning

confidence: 54%

“…Considering that the embryos were intact and embedded in agarose, we assume that the final drug concentrations were 10 times lower (Brustein et al, 2003;Brustein and Drapeau, 2005).…”

Section: Methodsmentioning

confidence: 99%

Neurogenic Role of the Depolarizing Chloride Gradient Revealed by Global Overexpression of KCC2 from the Onset of Development

Reynolds¹,

Brustein²,

Liao³

et al. 2008

J. Neurosci.

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“…Modulation of chloride homeostasis by 5-HT has been previously reported in the spinal cord [in zebrafish (31)] and several other systems (e.g., refs. 32 and 33).…”

Section: Discussionmentioning

confidence: 84%

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.

156

172

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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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“…In confirmation of this hypothesis, inhibition of Ca 2+ ‐dependent PKC (with nanomolar concentrations of Gö6976) abolished the 5‐HT 2 R‐dependent hyperpolarization of E GABA in neurons. It is also notable that serotonin activation of 5‐HT 2 Rs was previously reported to modulate Cl − homeostasis in zebrafish spinal cord neurons (Brustein and Drapeau 2005). …”

Section: Gpcr Modulation: a Brief Overviewmentioning

confidence: 88%

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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Serotoninergic Modulation of Chloride Homeostasis during Maturation of the Locomotor Network in Zebrafish

Cited by 42 publications

References 41 publications

Neurogenic Role of the Depolarizing Chloride Gradient Revealed by Global Overexpression of KCC2 from the Onset of Development

Neurogenic Role of the Depolarizing Chloride Gradient Revealed by Global Overexpression of KCC2 from the Onset of Development

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

Regulation of neuronal chloride homeostasis by neuromodulators

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