Mechanism of Activity-Dependent Downregulation of the Neuron-Specific K-Cl Cotransporter KCC2

Rivera, Claudio; Voipio, Juha; Thomas‐Crusells, Judith; Li, Hong; Emri, Zsuzsa; Sipilä, Sampsa T.; Payne, John A.; Minichiello, Liliana; Saarma, Märt; Kaila, Kai

doi:10.1523/jneurosci.5265-03.2004

Cited by 451 publications

(505 citation statements)

References 63 publications

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“…Our observation that the injury-associated reduction in KCC2 protein levels was transient paralleled the results in the hippocampus (Rivera et al, 2004) and provided further support for the notion that, like activity-dependent plasticity, nerve injury-associated pain exhibits early, intermediate and late phases of development which may be mediated by different receptors, signaling pathways, transcription factors and genes Malenka and Bear, 2004). …”

Section: Discussionsupporting

confidence: 78%

Loose ligation of the sciatic nerve is associated with TrkB receptor-dependent decreases in KCC2 protein levels in the ipsilateral spinal dorsal horn

Miletić¹,

Miletić²

2008

Pain

110

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Significant decreases in the protein levels of potassium-chloride co-transporter 2 (KCC2) were detected in the ipsilateral spinal dorsal horn 4h following loose ligation of the sciatic nerve. These decreases were associated with a change in hindlimb weight distribution suggestive of pain behavior. In contrast, no changes in GABA-A receptor subunit alpha-1 levels were detected. The decreases in KCC2 coincided with a significant ipsilateral increase in BDNF protein levels. Both the decreases in KCC2 levels and the early pain behavior were prevented by intrathecal pre-treatment with the BDNF-sequestering TrkB/Fc chimera protein or the tyrosine kinase blocker K252a. The ligationassociated decreases in KCC2 levels were transient. In the ipsilateral spinal dorsal horn of ligated animals exhibiting weight-bearing pain behavior 7 days after the ligation the KCC2 levels were identical to those in control or sham-operated animals. These data suggested that TrkB-dependent reduction in KCC2 protein levels in the spinal dorsal horn was an early consequence of peripheral nerve injury. This decrease in KCC2 may have elicited an early increase in overall dorsal horn neuronal excitability perhaps through a loss of GABA inhibition which is critically dependent on KCC2 activity. The increased neuronal excitability may in turn have caused enhanced and exaggerated communication between primary afferents and dorsal horn neurons to contribute to the early behavioral signs of pain.

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Section: Discussionsupporting

confidence: 78%

Loose ligation of the sciatic nerve is associated with TrkB receptor-dependent decreases in KCC2 protein levels in the ipsilateral spinal dorsal horn

Miletić¹,

Miletić²

2008

Pain

110

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“…Expression of immature features in the mature tissue might enhance neuron susceptibility to seizure activity. This is supported by a previous study (Rivera et al, 2004) showing an activity-dependent decrease in membrane expression of KCC2 protein. Therefore, susceptibility is expressed in the transcriptional downregulation of KCC2 as well as its functionality, determined by association to the membrane.…”

Section: Figuresupporting

confidence: 90%

“…Furthermore, this study suggests that KCC2 influences synchronization in the functional development of glutamatergic and GABAergic synapses in neurons. Moreover, KCC2 expression was shown to be correlated with synaptogenesis (Gulyás et al, 2001;Zhang et al, 2006), and fast kinetics of KCC2 activity regulation was shown (Kelsch et al, 2001;Rivera et al, 2004). Based on this, alterations in KCC2 may influence hippocampal and cortical plasticity and network activity, thereby affecting the trophic role of GABA in development (Ben-Ari, 2002;Owens and Kriegstein, 2002;Represa and Ben-Ari, 2005).…”

Section: Figurementioning

confidence: 94%

A Sensitive Period of Mice Inhibitory System to Neonatal GABA Enhancement by Vigabatrin is Brain Region Dependent

Levav-Rabkin

Melamed

Clarke

et al. 2009

Neuropsychopharmacol

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Neurodevelopmental disorders, such as schizophrenia and autism, have been associated with disturbances of the GABAergic system in the brain. We examined immediate and long-lasting influences of exposure to the GABA-potentiating drug vigabatrin (GVG) on the GABAergic system in the hippocampus and cerebral cortex, before and during the developmental switch in GABA function (postnatal days P1-7 and P4-14). GVG induced a transient elevation of GABA levels. A feedback response to GABA enhancement was evident by a short-term decrease in glutamate decarboxylase (GAD) 65 and 67 levels. However, the number of GAD65/67-immunoreactive (IR) cells was greater in 2-week-old GVG-treated mice. A long-term increase in GAD65 and GAD67 levels was dependent on brain region and treatment period. Vesicular GABA transporter was insensitive to GVG. The overall effect of GVG on the Cl À co-transporters NKCC1 and KCC2 was an enhancement of their synthesis, which was dependent on the treatment period and brain region studied. In addition, a short-term increase was followed by a long-term decrease in KCC2 oligomerization in the cell membrane of P4-14 hippocampi and cerebral cortices. Analysis of the Ca 2 + binding proteins expressed in subpopulations of GABAergic cells, parvalbumin and calbindin, showed region-specific effects of GVG during P4-14 on parvalbumin-IR cell density. Moreover, calbindin levels were elevated in GVG mice compared to controls during this period. Cumulatively, these results suggest a particular susceptibility of the hippocampus to GVG when exposed during days P4-14. In conclusion, our studies have identified modifications of key components in the inhibitory system during a critical developmental period. These findings provide novel insights into the deleterious consequences observed in children following prenatal and neonatal exposure to GABA-potentiating drugs.

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“…This view is supported by experimental evidence in which it was shown that following damage to afferents in the spinal cord, BDNF liberated by microglia activates trkB receptors leading to a KCC2 down-regulation and a depolarizing shift in GABAergic reversal potentials associated with pathological pain responses (Price et al, 2005;Lu et al, 2008). It has also been shown that experimentally induced interictal activity in hippocampal slices maintained in vitro, downregulates KCC2 mRNA and protein expression in CA1 pyramidal neurons, which leads to a reduced capacity for neuronal Cl − extrusion (Rivera et al, 2002(Rivera et al, , 2004Blaesse et al, 2009). Alterations in the balance of NKCC1 and KCC2 activity have also been identified in the subiculum and hippocampus of epileptic patients by Munoz et al (2007).…”

Section: Gaba a Receptor-mediated Inhibition May Implement Epileptifomentioning

confidence: 99%

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

Avoli¹,

Curtis²

2011

Progress in Neurobiology

227

253

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GABA is the main inhibitory neurotransmitter in the adult forebrain, where it activates ionotropic type A and metabotropic type B receptors. Early studies have shown that GABA A receptormediated inhibition controls neuronal excitability and thus the occurrence of seizures. However, more complex, and at times unexpected, mechanisms of GABAergic signaling have been identified during epileptiform discharges over the last few years. Here, we will review experimental data that point at the paradoxical role played by GABA A receptor-mediated mechanisms in synchronizing neuronal networks, and in particular those of limbic structures such as the hippocampus, the entorhinal and perirhinal cortices, or the amygdala. After having summarized the fundamental characteristics of GABA A receptor-mediated mechanisms, we will analyze their role in the generation of network oscillations and their contribution to epileptiform synchronization. Whether and how GABA A receptors influence the interaction between limbic networks leading to ictogenesis will be also reviewed. Finally, we will consider the role of altered inhibition in the human epileptic brain along with the ability of GABA A receptor-mediated conductances to generate synchronous depolarizing events that may lead to ictogenesis in human epileptic disorders as well.

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Mechanism of Activity-Dependent Downregulation of the Neuron-Specific K-Cl Cotransporter KCC2

Cited by 451 publications

References 63 publications

Loose ligation of the sciatic nerve is associated with TrkB receptor-dependent decreases in KCC2 protein levels in the ipsilateral spinal dorsal horn

Loose ligation of the sciatic nerve is associated with TrkB receptor-dependent decreases in KCC2 protein levels in the ipsilateral spinal dorsal horn

A Sensitive Period of Mice Inhibitory System to Neonatal GABA Enhancement by Vigabatrin is Brain Region Dependent

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

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