KNa1.1 gain-of-function preferentially dampens excitability of murine parvalbumin-positive interneurons

Gertler, Tracy S.; Cherian, Suraj; DeKeyser, Jean-Marc; Kearney, Jennifer A.; George, Alfred L.

doi:10.1016/j.nbd.2022.105713

Cited by 18 publications

(30 citation statements)

References 47 publications

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“…In such a case the effects of KCNT1 mutations on the neuronal excitability must be more pronounced in the inhibitory than the excitatory neurons. This corresponds well with the data obtained from mouse models of KCNT1-mediated epilepsy [ 16 , 17 ]. Importantly, the effects of T314A, which abolished voltage and Na + dependence (at least between 10 and 130 mM) of KCNT1, suggest that the pathogenicity of this mutation is due to increased resting K + conductance.…”

Section: Discussionsupporting

confidence: 89%

“…This notion is supported by the recent data obtained using a mouse model expressing human Y796H GoF KCNT1 , demonstrating that increased Na-dependent K + currents (Ik Na ) impair GABAergic neuron excitability and alter synaptic connectivity [ 16 ]. Another recent study of a mouse model expressing L437F GoF KCNT1 has revealed that KCNT1 channels are predominantly expressed in GABAergic parvalbumin-positive interneurons of the hippocampus, which exhibit a significantly reduced excitability, compared to this type of interneurons in the WT mice [ 17 ]. In contrast, data obtained from induced pluripotent stem cells (iPSC)-derived neurons expressing homozygous KCNT1 P924L GoF mutation suggest the possibility of a different mechanism [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

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Functional Effects of Epilepsy Associated KCNT1 Mutations Suggest Pathogenesis via Aberrant Inhibitory Neuronal Activity

Rychkov

Shaukat

Lim

et al. 2022

IJMS

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KCNT1 (K+ channel subfamily T member 1) is a sodium-activated potassium channel highly expressed in the nervous system which regulates neuronal excitability by contributing to the resting membrane potential and hyperpolarisation following a train of action potentials. Gain of function mutations in the KCNT1 gene are the cause of neurological disorders associated with different forms of epilepsy. To gain insights into the underlying pathobiology we investigated the functional effects of 9 recently published KCNT1 mutations, 4 previously studied KCNT1 mutations, and one previously unpublished KCNT1 variant of unknown significance. We analysed the properties of KCNT1 potassium currents and attempted to find a correlation between the changes in KCNT1 characteristics due to the mutations and severity of the neurological disorder they cause. KCNT1 mutations identified in patients with epilepsy were introduced into the full length human KCNT1 cDNA using quick-change site-directed mutagenesis protocol. Electrophysiological properties of different KCNT1 constructs were investigated using a heterologous expression system (HEK293T cells) and patch clamping. All mutations studied, except T314A, increased the amplitude of KCNT1 currents, and some mutations shifted the voltage dependence of KCNT1 open probability, increasing the proportion of channels open at the resting membrane potential. The T314A mutation did not affect KCNT1 current amplitude but abolished its voltage dependence. We observed a positive correlation between the severity of the neurological disorder and the KCNT1 channel open probability at resting membrane potential. This suggests that gain of function KCNT1 mutations cause epilepsy by increasing resting potassium conductance and suppressing the activity of inhibitory neurons. A reduction in action potential firing in inhibitory neurons due to excessively high resting potassium conductance leads to disinhibition of neural circuits, hyperexcitability and seizures.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Functional Effects of Epilepsy Associated KCNT1 Mutations Suggest Pathogenesis via Aberrant Inhibitory Neuronal Activity

Rychkov

Shaukat

Lim

et al. 2022

IJMS

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“…The voltage-dependence of the increased K Na current was different in GABAergic and glutamatergic neurons. In GABAergic neurons, significant increases in K Na current were detected at more negative membrane potentials than in glutamatergic neurons, suggesting that the Slack-R455H mutation modifies the intrinsic excitability of GABAergic neurons near the resting potential, hyperpolarizing the neurons and reducing excitability 8,9,12,13 . Conversely in glutamatergic neurons of Slack-R455H , the increased K Na current activates selectively at higher membrane potentials such as those reached only during action potentials, shortening the action potentials and limiting Na + channel inactivation.…”

Section: Discussionmentioning

confidence: 99%

“…The extracellular medium contained the following (in mM): either 140 NaCl or 140 N-methyl-D-glucamine (NMDG), 5.4 KCl, 10 HEPES, 10 glucose, 1 MgCl 2 , and 1 CaCl 2 (pH 7.4, 310 mOsm). K Na currents and TTX-sensitive K + currents were recorded according to the protocols reported in previous studies 5,13 . Neurons were held at -80 mV and given 60 ms voltage pulses in 10 mV steps over a range of -90 to +50 mV.…”

Section: Supplementary Informationmentioning

confidence: 99%

“…Enhanced excitation in excitatory neurons and/or inhibition in inhibitory interneurons would result in hyperactivity of the epileptic circuitry 16,17 . Two recent studies have shown that excitability and AP generation of inhibitory interneuron, but not excitatory neuron, were impaired by Slack GOF variants, leading to loss of inhibitory regulation and seizure susceptibility 12,13 , suggesting that Slack GOF variants may have different effects on the excitability of the two specific neuron types. However, in contrast to the situation in humans, where a mutation in a single copy of the Slack ( Kcnt1 ) gene results in serious disease, the mouse models used in these studies were homozygous for the channel mutations.…”

Section: Introductionmentioning

confidence: 99%

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Disease-causing Slack potassium channel mutations produce opposite effects on excitability of excitatory and inhibitory neurons

Quraishi

Zhang

et al. 2023

Preprint

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KCNT1 encodes the sodium-activated potassium channel Slack (KCNT1, KNa1.1), an important mediator of neuronal membrane excitability. Gain-of-function (GOF) mutations in humans lead cortical network hyperexcitability and seizures, as well as very severe intellectual disability. Using a mouse model of Slack GOF-associated epilepsy, we found that both excitatory and inhibitory neurons of the cerebral cortex have increased Na+-dependent K+ (KNa) currents and voltage-dependent sodium (NaV) currents. The characteristics of the increased KNa currents were, however, different in the two cell types such that the intrinsic excitability of excitatory neurons was enhanced but that of inhibitory neurons was suppressed. We further showed that the expression of NaV channel subunits, particularly that of NaV1.6, is upregulated and that the length of the axon initial segment (AIS) and of axonal NaV immunostaining is increased in both neuron types. We found that the proximity of the AIS to the soma is shorter in excitatory neurons than in inhibitory neurons of the mutant animals, potentially contributing to the different effects on membrane excitability. Our study on the coordinate regulation of KNa currents and the expression of NaV channels may provide a new avenue for understanding and treating epilepsies and other neurological disorders.

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Potassium channelopathies associated with epilepsy-related syndromes and directions for therapeutic intervention

Gribkoff

Winquist

2023

Biochemical Pharmacology

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KNa1.1 gain-of-function preferentially dampens excitability of murine parvalbumin-positive interneurons

Cited by 18 publications

References 47 publications

Functional Effects of Epilepsy Associated KCNT1 Mutations Suggest Pathogenesis via Aberrant Inhibitory Neuronal Activity

Functional Effects of Epilepsy Associated KCNT1 Mutations Suggest Pathogenesis via Aberrant Inhibitory Neuronal Activity

Disease-causing Slack potassium channel mutations produce opposite effects on excitability of excitatory and inhibitory neurons

Potassium channelopathies associated with epilepsy-related syndromes and directions for therapeutic intervention

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