Enhanced expression of potassium-chloride cotransporter KCC2 in human temporal lobe epilepsy

Karlócai, Mária R.; Wittner, Lúcia; Tóth, Kinga; Maglóczky, Zsófia; Katarova, Zója; Rásonyi, György; Erőss, Lóránd; Czirják, Sándor; Halász, Péter; Szabó, Gábor; Payne, John A.; Kaila, Kai; Freund, Tamás F.

doi:10.1007/s00429-015-1122-8

Cited by 32 publications

(23 citation statements)

References 94 publications

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“…A higher local Cl À turnover would be necessary to sustain inhibition in an overactive network, and prevent a significant alteration of the steady state Cl À levels. This explanation would be consistent with the observation that in chronic epileptic conditions (Pathak et al, 2007;Karlo´cai et al, 2016), or peritumoral tissue (Conti et al, 2011), the KCC2 amounts usually increase, which points to a long-term compensation of hyperexcitability. In fact, deleting KCC2 in mice facilitates epileptiform activity (Woo et al, 2002;Tornberg et al, 2005), and mutations impairing KCC2 are linked to human epilepsy (Kahle et al, 2014;Puskarjov et al, 2014).…”

Section: The Effect Of B2-v287l On Cotransporters' Amounts and The Gasupporting

confidence: 89%

“…Epilepsy, however, comprises a heterogeneous spectrum of disorders (Jensen, 2011). The role of NKCC1 and KCC2 has been extensively studied in parietal and temporal lobe epilepsy (Dzhala et al, 2005;Aronica et al, 2007;Pathak et al, 2007;Li et al, 2008;Zhu et al, 2008;Talos et al, 2012;Awad et al, 2016;Karlo´cai et al, 2016), but not in frontal epilepsy. The latter presents distinct pathophysiological features, particularly in relation to the sleep-waking cycle.…”

Section: Introductionmentioning

confidence: 99%

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Postnatal Changes in K+/Cl− Cotransporter-2 Expression in the Forebrain of Mice Bearing a Mutant Nicotinic Subunit Linked to Sleep-Related Epilepsy

et al. 2018

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The Na/K/Cl cotransporter-1 (NKCC1) and the K/Cl cotransporter-2 (KCC2) set the transmembrane Cl gradient in the brain, and are implicated in epileptogenesis. We studied the postnatal distribution of NKCC1 and KCC2 in wild-type (WT) mice, and in a mouse model of sleep-related epilepsy, carrying the mutant β2-V287L subunit of the nicotinic acetylcholine receptor (nAChR). In WT neocortex, immunohistochemistry showed a wide distribution of NKCC1 in neurons and astrocytes. At birth, KCC2 was localized in neuronal somata, whereas at subsequent stages it was mainly found in the somatodendritic compartment. The cotransporters' expression was quantified by densitometry in the transgenic strain. KCC2 expression increased during the first postnatal weeks, while the NKCC1 amount remained stable, after birth. In mice expressing β2-V287L, the KCC2 amount in layer V of prefrontal cortex (PFC) was lower than in the control littermates at postnatal day 8 (P8), with no concomitant change in NKCC1. Consistently, the GABAergic excitatory to inhibitory switch was delayed in PFC layer V of mice carrying β2-V287L. At P60, the amount of KCC2 was instead higher in mice bearing the transgene. Irrespective of genotype, NKCC1 and KCC2 were abundantly expressed in the neuropil of most thalamic nuclei since birth. However, KCC2 expression decreased by P60 in the reticular nucleus, and more so in mice expressing β2-V287L. Therefore, a complex regulatory interplay occurs between heteromeric nAChRs and KCC2 in postnatal forebrain. The pathogenetic effect of β2-V287L may depend on altered KCC2 amounts in PFC during synaptogenesis, as well as in mature thalamocortical circuits.

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Section: The Effect Of B2-v287l On Cotransporters' Amounts and The Gasupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Postnatal Changes in K+/Cl− Cotransporter-2 Expression in the Forebrain of Mice Bearing a Mutant Nicotinic Subunit Linked to Sleep-Related Epilepsy

et al. 2018

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“…A similar KCC2 deficiency in cornu ammonis 1 (CA1) pyramidal neurons leads to formation of hypertrophic PV + baskets adjacent to the sclerotic areas of patients with an epileptic hippocampus (84). Alterations of chloride cotransporters and aberrant GABAergic hyperinnervation can lead to an increased propensity for seizures, a prominent signature in ASDs, including RTT (85)(86)(87), which is also seen in mouse models of RTT (18)(19)(20).…”

Section: Discussionmentioning

confidence: 99%

Jointly reduced inhibition and excitation underlies circuit-wide changes in cortical processing in Rett syndrome

Banerjee

Rikhye

Breton-Provencher

et al. 2016

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

159

202

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Rett syndrome (RTT) arises from loss-of-function mutations in methyl-CpG binding protein 2 gene (Mecp2), but fundamental aspects of its physiological mechanisms are unresolved. Here, by whole-cell recording of synaptic responses in MeCP2 mutant mice in vivo, we show that visually driven excitatory and inhibitory conductances are both reduced in cortical pyramidal neurons. The excitation-to-inhibition (E/I) ratio is increased in amplitude and prolonged in time course. These changes predict circuit-wide reductions in response reliability and selectivity of pyramidal neurons to visual stimuli, as confirmed by two-photon imaging. and increases KCC2 expression to normalize the KCC2/NKCC1 ratio. Thus, loss of MeCP2 in the brain alters both excitation and inhibition in brain circuits via multiple mechanisms. Loss of MeCP2 from a specific interneuron subtype contributes crucially to the cell-specific and circuit-wide deficits of RTT. The joint restoration of inhibition and excitation in cortical circuits is pivotal for functionally correcting the disorder.MeCP2 | E/I balance | parvalbumin neurons | IGF1 | chloride transporters S ynaptic excitation (E) and inhibition (I), along with the neuronal balance of excitation and inhibition (E/I), is key to the function of brain circuits, and is often disrupted in neurodevelopmental disorders, including autism spectrum disorders (ASDs) (1-3). Rett syndrome (RTT) is a severe neurodevelopmental and adult disorder that arises from sporadic loss-of-function mutations in the X-linked (Xq28) methyl-CpG binding protein 2 gene (Mecp2) encoding the protein MeCP2 (4-7). MeCP2 is a critical regulator of brain development and adult neural function (8), and arrested brain maturation due to synaptic dysfunction is one of the hallmarks of RTT (3). However, the effects of MeCP2 on excitatory and inhibitory synaptic mechanisms in vivo, and on neuronal and circuit function underlying RTT pathophysiology, are unknown.MeCP2 is ubiquitously expressed in multiple cell types and subregions of the brain (4, 6, 9), including inhibitory interneurons, and has cell-autonomous as well as non-cell-autonomous effects (10); thus, it has been particularly challenging to identify its role in cell-specific brain circuits. Anatomically diverse inhibitory interneuron subtypes with distinct physiological signatures influence different aspects of neocortical function and behavior (11,12). Soma-targeting parvalbumin-expressing (PV + ) and dendritetargeting somatostatin-expressing (SOM + ) interneurons are the two major nonoverlapping populations of interneurons in mice that target cortical pyramidal neurons (13). Inhibition by PV + and SOM + neurons powerfully influences neuronal responses and circuit computations in visual cortex (14-17). Deletion of MeCP2 from all forebrain GABAergic interneurons recapitulates key aspects of RTT (18), demonstrating that altered inhibitory function is an important facet of RTT pathophysiology. Indeed, a major phenotype of MeCP2 reduction in individuals with RTT and in mouse models is ...

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“…CCC expression is altered in a variety of neurological and psychiatric conditions including epilepsy (Palma et al , 2006; Huberfeld et al , 2007; Karlocai et al , 2016; Kourdougli et al , 2017), chronic stress (MacKenzie & Maguire, 2015), Rett syndrome (Duarte et al , 2013; Banerjee et al , 2016; Tang et al , 2016) and autism spectrum disorders (Tyzio et al , 2014). Impaired chloride homeostasis has been suggested to induce paradoxical excitatory GABA signaling and thereby promote anomalous ensemble activities that underlie the pathology.…”

Section: Discussionmentioning

confidence: 99%

Cation-chloride cotransporters and the polarity of GABA signaling in mouse hippocampal parvalbumin interneurons

Otsu

Donneger

Schwartz

et al. 2019

Preprint

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Transmembrane chloride gradients govern the efficacy and polarity of GABA signaling in neurons and are usually maintained by the activity of cation chloride cotransporters, such as KCC2 and NKCC1. Whereas their role is well established in cortical principal neurons, it remains poorly documented in GABAergic interneurons. We used complementary electrophysiological approaches to compare the effects of GABAAR activation in adult mouse hippocampal parvalbumin interneurons (PV INs) and pyramidal cells (PCs). Loose cell attached, tight-seal and gramicidin-perforated patch recordings all show GABAAR-mediated transmission is slightly depolarizing and yet inhibitory in both PV INs and PCs. Focal GABA uncaging in whole-cell recordings reveal that KCC2 and NKCC1 are functional in both PV INs and PCs but differentially contribute to transmembrane chloride gradients in their soma and dendrites. Blocking KCC2 function depolarizes the reversal potential of GABAAR-mediated currents in PV INs and PCs, often beyond firing threshold, showing KCC2 is essential to maintain the inhibitory effect of GABAARs. Finally, we show that repetitive 10 Hz activation of GABAARs in both PV INs and PCs leads to a progressive decline of the postsynaptic response independently of the ion flux direction or KCC2 function. This suggests intraneuronal chloride buildup may not predominantly contribute to activity-dependent plasticity of GABAergic synapses in this frequency range. Altogether our data demonstrate similar mechanisms of chloride regulation in mouse hippocampal PV INs and PCs and suggest KCC2 downregulation in the pathology may affect the valence of GABA signaling in both cell types.Key point summaryCation-chloride cotransporters (CCCs) play a critical role in controlling the efficacy and polarity of GABAA receptor (GABAAR)-mediated transmission in the brain, yet their expression and function in GABAergic interneurons has been overlooked.We compared the polarity of GABA signaling and the function of CCCs in mouse hippocampal pyramidal neurons and parvalbumin-expressing interneurons.Under resting conditions, GABAAR activation was mostly depolarizing and yet inhibitory in both cell types. KCC2 blockade further depolarized the reversal potential of GABAAR-mediated currents often above action potential threshold.However, during repetitive GABAAR activation, the postsynaptic response declined independently of the ion flux direction or KCC2 function, suggesting intracellular chloride buildup is not responsible for this form of plasticity.Our data demonstrate similar mechanisms of chloride regulation in mouse hippocampal pyramidal neurons and parvalbumin interneurons.

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Enhanced expression of potassium-chloride cotransporter KCC2 in human temporal lobe epilepsy

Cited by 32 publications

References 94 publications

Postnatal Changes in K+/Cl− Cotransporter-2 Expression in the Forebrain of Mice Bearing a Mutant Nicotinic Subunit Linked to Sleep-Related Epilepsy

Postnatal Changes in K+/Cl− Cotransporter-2 Expression in the Forebrain of Mice Bearing a Mutant Nicotinic Subunit Linked to Sleep-Related Epilepsy

Jointly reduced inhibition and excitation underlies circuit-wide changes in cortical processing in Rett syndrome

Cation-chloride cotransporters and the polarity of GABA signaling in mouse hippocampal parvalbumin interneurons

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