Developmental Expression Patterns of KCC2 and Functionally Associated Molecules in the Human Brain

Sedmak, Goran; Jovanov-Milošević, Nataša; Puskarjov, Martin; Ulamec, Monika; Krušlin, Božo; Kaila, Kai; Judaš, Miloš

doi:10.1093/cercor/bhv218

Cited by 103 publications

(93 citation statements)

References 140 publications

(270 reference statements)

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“…Developmentally, the NKCC1 transporter was thought to be expressed earlier than KCC2 which explained the high [Cl − ] i observed at this age [35–37], while KCC2 was considered to be expressed later during development [38,39,37,40]. However, recent studies suggest that both NKCC1 and KCC2 are expressed outside these developmental windows [41]. Thus, these new results argue against the notion that the expressed transporter species determine the [Cl − ] i .…”

Section: [Cl−]i During Development: a Tale Of Two Transportersmentioning

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−]i During Development: a Tale Of Two Transportersmentioning

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 data on the developmental changes in NKCC1 and KCC2 expression in the human brain are inconsistent. An earlier report indicated that the human cortex undergoes similar developmental changes during the perinatal period [6], whereas recent systematic studies have shown that KCC2 upregulation starts early in the prenatal period and reaches a high level at birth [3, 37, 38]. However, GABAergic anti-convulsants are shown to be less effective in the inhibition of cortical seizure activity than in the inhibition of motor activity in neonatal seizure [39, 40], suggesting similar differential maturation of GABA A receptor signaling between the rostral and caudal CNS in humans.…”

Section: Discussionmentioning

confidence: 99%

Bumetanide, an Inhibitor of NKCC1 (Na-K-2Cl Cotransporter Isoform 1), Enhances Propofol-Induced Loss of Righting Reflex but Not Its Immobilizing Actions in Neonatal Rats

et al. 2016

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Gamma-aminobutyric acid (GABA) has been shown to induce excitation on immature neurons due to increased expression of Na+-K+-2Cl- co-transporter isoform 1 (NKCC1), and the transition of GABAergic signaling from excitatory to inhibitory occurs before birth in the rat spinal cord and spreads rostrally according to the developmental changes in cation-chloride co-transporter expression. We previously showed that midazolam activates the hippocampal CA3 area and induces less sedation in neonatal rats compared with adolescent rats in an NKCC1-dependent manner. In the present study, we tested the hypothesis that propofol-induced loss of righting reflex (LORR) but not immobilizing actions are modulated by NKCC1-dependent mechanisms and reduced in neonatal rats compared with adolescent rats. We estimated neuronal activity in the cortex, hippocampus and thalamus after propofol administration with or without bumetanide, an NKCC1 inhibitor, by immunostaining of phosphorylated cyclic adenosine monophosphate-response element binding protein (pCREB). We studied effects of bumetanide on propofol-induced LORR and immobilizing actions in postnatal day 7 and 28 (P7 and P28) rats. The pCREB expression in the cortex (P = 0.001) and hippocampus (P = 0.01) was significantly greater in the rats receiving propofol only than in the rats receiving propofol plus bumetanide at P 7. Propofol-induced LORR or immobilizing effects did not differ significantly between P7 and P28. Bumetanide significantly enhanced propofol-induced LORR (P = 0.031) but not immobilization in P7 rats. These results are partially consistent with our hypothesis. They suggest that propofol may activate the rostral but not caudal central nervous system dependently on NKCC1, and these differential actions may underlie the different properties of sedative and immobilizing actions observed in neonatal rats.

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“…), and is considered to be the isoform responsible for the developmental shift in the GABAergic response; this developmental shift in humans takes place at the beginning of the last trimester of gestation (Sedmak et al . ). KCC2b differs in its 5′‐untranslated region and 5′‐coding region compared to KCC2a.…”

Section: Chloride Co‐transportersmentioning

confidence: 97%

“…), yet developmental up‐regulation of KCC2 is seen in the vast majority of central nervous system neurons (Sedmak et al . ).…”

Section: Chloride Co‐transportersmentioning

confidence: 97%

Chloride co‐transporters as possible therapeutic targets for stroke

Baudel

Poole

Darlison

2016

Journal of Neurochemistry

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Stroke is one of the major causes of death and disability worldwide. The major type of stroke is an ischaemic one, which is caused by a blockage that interrupts blood flow to the brain. There are currently very few pharmacological strategies to reduce the damage and social burden triggered by this pathology. The harm caused by the interruption of blood flow to the brain unfolds in the subsequent hours and days, so it is critical to identify new therapeutic targets that could reduce neuronal death associated with the spread of the damage. Here, we review some of the key molecular mechanisms involved in the progression of neuronal death, focusing on some new and promising studies. In particular, we focus on the potential of the chloride co-transporter (CCC) family of proteins, mediators of the GABAergic response, both during the early and later stages of stroke, to promote neuroprotection and recovery. Different studies of CCCs during the chronic and recovery phases post-stroke reveal the importance of timing when considering CCCs as potential neuroprotective and/or neuromodulator targets. The molecular regulatory mechanisms of the two main neuronal CCCs, NKCC1 and KCC2, are further discussed as an indirect approach for promoting neuroprotection and neurorehabilitation following an ischaemic insult. Finally, we mention the likely importance of combining different strategies in order to achieve more effective therapies.

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Developmental Expression Patterns of KCC2 and Functionally Associated Molecules in the Human Brain

Cited by 103 publications

References 140 publications

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

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

Bumetanide, an Inhibitor of NKCC1 (Na-K-2Cl Cotransporter Isoform 1), Enhances Propofol-Induced Loss of Righting Reflex but Not Its Immobilizing Actions in Neonatal Rats

Chloride co‐transporters as possible therapeutic targets for stroke

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