Deletion of the Na-K-2Cl cotransporter NKCC1 results in a more severe epileptic phenotype in the intrahippocampal kainate mouse model of temporal lobe epilepsy

Hampel, Philip; Johne, Marie; Gailus, Björn; Vogel, Alexandra; Schidlitzki, Alina; Gericke, Birthe; Töllner, Kathrin; Theilmann, Wiebke; Käufer, Christopher; Römermann, Kerstin; Kaila, Kai; Löscher, Wolfgang

doi:10.1016/j.nbd.2021.105297

Cited by 11 publications

(9 citation statements)

References 73 publications

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“…Kcc2 downregulation is also observed in VPA-induced rodent models of autism and neurons derived from patients with Rett syndrome ( Duarte et al, 2013 ; Banerjee et al, 2016 ; Tang et al, 2016 ; Hinz et al, 2019 ). Finally, both rodent and human temporal lobe epilepsy studies show upregulated Nkcc1 and downregulated Kcc2 ( Karlócai et al, 2016 ; Auer et al, 2020 ; Hampel et al, 2021 ). These findings are especially important as these neurodevelopment disorders share a common comorbidity of increased seizure susceptibility, which is speculated to be a cortical manifestation of runaway hyperexcitability produced by E/I imbalance ( Canitano, 2007 ; González and Bautista, 2009 ; Glaze et al, 2010 ; He et al, 2014 ; Ruffolo et al, 2016 ).…”

Section: Chloride Transporter Expression Underlies the Gabaergic Pola...mentioning

confidence: 97%

Chloride imbalance in Fragile X syndrome

Miles

Doll²

2022

Front. Neurosci.

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Developmental changes in ionic balance are associated with crucial hallmarks in neural circuit formation, including changes in excitation and inhibition, neurogenesis, and synaptogenesis. Neuronal excitability is largely mediated by ionic concentrations inside and outside of the cell, and chloride (Cl–) ions are highly influential in early neurodevelopmental events. For example, γ-aminobutyric acid (GABA) is the main inhibitory neurotransmitter of the mature central nervous system (CNS). However, during early development GABA can depolarize target neurons, and GABAergic depolarization is implicated in crucial neurodevelopmental processes. This developmental shift of GABAergic neurotransmission from depolarizing to hyperpolarizing output is induced by changes in Cl– gradients, which are generated by the relative expression of Cl– transporters Nkcc1 and Kcc2. Interestingly, the GABA polarity shift is delayed in Fragile X syndrome (FXS) models; FXS is one of the most common heritable neurodevelopmental disorders. The RNA binding protein FMRP, encoded by the gene Fragile X Messenger Ribonucleoprotein-1 (Fmr1) and absent in FXS, appears to regulate chloride transporter expression. This could dramatically influence FXS phenotypes, as the syndrome is hypothesized to be rooted in defects in neural circuit development and imbalanced excitatory/inhibitory (E/I) neurotransmission. In this perspective, we summarize canonical Cl– transporter expression and investigate altered gene and protein expression of Nkcc1 and Kcc2 in FXS models. We then discuss interactions between Cl– transporters and neurotransmission complexes, and how these links could cause imbalances in inhibitory neurotransmission that may alter mature circuits. Finally, we highlight current therapeutic strategies and promising new directions in targeting Cl– transporter expression in FXS patients.

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Section: Chloride Transporter Expression Underlies the Gabaergic Pola...mentioning

confidence: 97%

Chloride imbalance in Fragile X syndrome

Miles

Doll²

2022

Front. Neurosci.

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“…Astrocytic NKCC1 is upregulated in response to trauma (Jayakumar et al, 2011) and both inhibiting NKCC1 activity pharmacologically with bumetanide or genetically with an anti-NKCC1 siRNA significantly reduces trauma-induced increase in astrocytic volume. It is worth mentioning that the Slc12a2 KO mouse is viable (Delpire et al, 1999;Dixon et al, 1999;Flagella et al, 1999); however, the loss of the NKCC1 protein causes deficits in neuronal proliferation (Magalhães and Rivera, 2016) and exacerbates the severity of a mouse model of epilepsy (Hampel et al, 2021), amongst other issues. Whereas neuronal loss of NKCC1 appears to be compensated for at the network level (Sipila et al, 2009), the consequences on glia are much less clear.…”

Section: Glial Contributions To Chloride Regulationmentioning

confidence: 99%

How Staying Negative Is Good for the (Adult) Brain: Maintaining Chloride Homeostasis and the GABA-Shift in Neurological Disorders

Hui

Chater

Goda

et al. 2022

Front. Mol. Neurosci.

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Excitatory-inhibitory (E-I) imbalance has been shown to contribute to the pathogenesis of a wide range of neurodevelopmental disorders including autism spectrum disorders, epilepsy, and schizophrenia. GABA neurotransmission, the principal inhibitory signal in the mature brain, is critically coupled to proper regulation of chloride homeostasis. During brain maturation, changes in the transport of chloride ions across neuronal cell membranes act to gradually change the majority of GABA signaling from excitatory to inhibitory for neuronal activation, and dysregulation of this GABA-shift likely contributes to multiple neurodevelopmental abnormalities that are associated with circuit dysfunction. Whilst traditionally viewed as a phenomenon which occurs during brain development, recent evidence suggests that this GABA-shift may also be involved in neuropsychiatric disorders due to the “dematuration” of affected neurons. In this review, we will discuss the cell signaling and regulatory mechanisms underlying the GABA-shift phenomenon in the context of the latest findings in the field, in particular the role of chloride cotransporters NKCC1 and KCC2, and furthermore how these regulatory processes are altered in neurodevelopmental and neuropsychiatric disorders. We will also explore the interactions between GABAergic interneurons and other cell types in the developing brain that may influence the GABA-shift. Finally, with a greater understanding of how the GABA-shift is altered in pathological conditions, we will briefly outline recent progress on targeting NKCC1 and KCC2 as a therapeutic strategy against neurodevelopmental and neuropsychiatric disorders associated with improper chloride homeostasis and GABA-shift abnormalities.

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“…For instance, we found very recently that constitutive disruption of expression of the Slc12a2 gene, which codes for NKCC1, leads to enhanced severity of seizures in the widely used kainate model of temporal lobe epilepsy. 43 Interestingly, systemic administration of bumetanide has an anti-inflammatory action outside the brain, whereas direct application into the brain in vivo has the opposite effect. 44 There are also intriguing findings obtained using low systemic doses of bumetanide and other diuretics in rodents (e.g., Krystal et al, 45 and Marguet et al 46 ) that point to beneficial actions, based on unidentified mechanisms outside the brain.…”

Section: Bumetanide Outside the Brainmentioning

confidence: 99%

“…Therefore, nonspecific manipulation of NKCC1 in the organism can lead to unexpected effects, and especially so if research is based on the outdated dogma referred to above. For instance, we found very recently that constitutive disruption of expression of the Slc12a2 gene, which codes for NKCC1, leads to enhanced severity of seizures in the widely used kainate model of temporal lobe epilepsy 43 …”

Section: Cellular Targets Of Bumetanide Outside the Brainmentioning

confidence: 99%

Reply to the commentary by Ben‐Ari and Delpire: Bumetanide and neonatal seizures: Fiction versus reality

Löscher

Kaila

2021

Epilepsia

Self Cite

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In this response to a commentary by Ben‐Ari and Delpire on our recent study on the pharmacology of neonatal seizures in a novel, physiologically validated rat model of birth asphyxia, we wish to rectify their inaccurate descriptions of our model and data. Furthermore, because Ben‐Ari and Delpire suggest that negative data on bumetanide from preclinical and clinical trials of neonatal seizures have few implications for (alleged) bumetanide actions on neurons in other brain disorders, we will discuss this topic as well. Based on the poor brain penetration of bumetanide, combined with the extremely wide cellular expression patterns of the target protein NKCC1, it is obvious that the numerous actions of systemically applied bumetanide described in the literature are not mediated by the drug's effects on central neurons.

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Deletion of the Na-K-2Cl cotransporter NKCC1 results in a more severe epileptic phenotype in the intrahippocampal kainate mouse model of temporal lobe epilepsy

Cited by 11 publications

References 73 publications

Chloride imbalance in Fragile X syndrome

Chloride imbalance in Fragile X syndrome

How Staying Negative Is Good for the (Adult) Brain: Maintaining Chloride Homeostasis and the GABA-Shift in Neurological Disorders

Reply to the commentary by Ben‐Ari and Delpire: Bumetanide and neonatal seizures: Fiction versus reality

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