Paradoxical hyperexcitability from NaV1.2 sodium channel loss in neocortical pyramidal cells

Spratt, Perry W.E.; Alexander, Ryan P.D.; Ben-Shalom, Roy; Sahagun, Atehsa; Kyoung, Henry; Keeshen, Caroline M.; Sanders, Stephan J.; Bender, Kevin J.

doi:10.1016/j.celrep.2021.109483

Cited by 60 publications

(79 citation statements)

References 52 publications

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“…Overall, by complementarily employing the LCA and whole-cell patch-clamp electrophysiology in heterologous cells, we have demonstrated that pharmacological inhibition of Wee1 kinase confers modulatory effects on the Na v 1.2, but not the Na v 1.6, macromolecular complex. As both of these Na v channel isoforms are enriched in clinically relevant brain re-gions with different subcellular distributions [46], our findings have important implications for understanding cellular signaling molecules that fine-tune neuronal excitability.…”

Section: Discussionmentioning

confidence: 90%

“…In particular, and given the selective effects of Wee1 inhibitor II on FGF14-mediated regulation of the Na v 1.2 channel, but not the Na v 1.6 channel, our data suggest that Wee1 kinase could confer targeted subcellular regulation of neuronal activity. Such a hypothesis is supported by Na v 1.2 channels being enriched in the somatodendritic region and proximal axon initial segment of neurons where they contribute to action potential backpropagation and spike timing-dependent plasticity, whereas Na v 1.6 channels are enriched in the distal region of the axon initial segment where they contribute to the forward propagation of action potentials and repetitive firing [46][47][48][49]. As such, our data suggest that Wee1 kinase might have an important role in promoting action potential backpropagation and synaptic signal integration, although, future ex vivo current-clamp recordings would be necessary to validate such regulatory mechanisms [47].…”

Section: Discussionmentioning

confidence: 99%

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Pharmacological Inhibition of Wee1 Kinase Selectively Modulates the Voltage-Gated Na+ Channel 1.2 Macromolecular Complex

Dvorak

Tapia

Baumgartner

et al. 2021

Cells

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Voltage-gated Na+ (Nav) channels are a primary molecular determinant of the action potential (AP). Despite the canonical role of the pore-forming α subunit in conferring this function, protein–protein interactions (PPI) between the Nav channel α subunit and its auxiliary proteins are necessary to reconstitute the full physiological activity of the channel and to fine-tune neuronal excitability. In the brain, the Nav channel isoforms 1.2 (Nav1.2) and 1.6 (Nav1.6) are enriched, and their activities are differentially regulated by the Nav channel auxiliary protein fibroblast growth factor 14 (FGF14). Despite the known regulation of neuronal Nav channel activity by FGF14, less is known about cellular signaling molecules that might modulate these regulatory effects of FGF14. To that end, and building upon our previous investigations suggesting that neuronal Nav channel activity is regulated by a kinase network involving GSK3, AKT, and Wee1, we interrogate in our current investigation how pharmacological inhibition of Wee1 kinase, a serine/threonine and tyrosine kinase that is a crucial component of the G2-M cell cycle checkpoint, affects the Nav1.2 and Nav1.6 channel macromolecular complexes. Our results show that the highly selective inhibitor of Wee1 kinase, called Wee1 inhibitor II, modulates FGF14:Nav1.2 complex assembly, but does not significantly affect FGF14:Nav1.6 complex assembly. These results are functionally recapitulated, as Wee1 inhibitor II entirely alters FGF14-mediated regulation of the Nav1.2 channel, but displays no effects on the Nav1.6 channel. At the molecular level, these effects of Wee1 inhibitor II on FGF14:Nav1.2 complex assembly and FGF14-mediated regulation of Nav1.2-mediated Na+ currents are shown to be dependent upon the presence of Y158 of FGF14, a residue known to be a prominent site for phosphorylation-mediated regulation of the protein. Overall, our data suggest that pharmacological inhibition of Wee1 confers selective modulatory effects on Nav1.2 channel activity, which has important implications for unraveling cellular signaling pathways that fine-tune neuronal excitability.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Pharmacological Inhibition of Wee1 Kinase Selectively Modulates the Voltage-Gated Na+ Channel 1.2 Macromolecular Complex

Dvorak

Tapia

Baumgartner

et al. 2021

Cells

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“…The RNA-seq data of WT juvenile mice indicated abundant expression of Na V 1.2 and Na V 1.6 in these neurons ( Scn2a : ∼120 FPKM; Scn8a : ∼90 FPKM), low expression of Na V 1.3 ( Scn3a : ∼11 FPKM), and intermediate expression of Na V 1.1 ( Scn1a : ∼40 FPKM, 4.5-fold lower compared to their expression in SO interneurons) ( Cembrowski et al, 2016 ). While Na V 1.6 and Na V 1.2 are the predominant sodium channels found in the AIS ( Hu et al, 2009 ; Lorincz and Nusser, 2010 ; Katz et al, 2018 ), and Na V 1.2 are the primary dendritic sodium channels ( Spratt et al, 2021 ), the spatial expression of Na V 1.1 in these cells remains poorly defined, with evidence supporting somato-dendritic expression ( Westenbroek et al, 1989 ; Yu et al, 2006 ). Since Hm1a shows some activity also toward Na V 1.2 channels ( Chever et al, 2021 ), and due to the high dendritic expression of these channels in CA1 pyramidal neurons ( Cembrowski et al, 2016 ), we cannot exclude the possibility that the reduced effect of Hm1a in DS Scn1a A1783V/WT is governed by alterations in the functional expression of Na V 1.1 and Na V 1.2 ( Figures 2 , 4A–D ).…”

Section: Discussionmentioning

confidence: 99%

Functional Investigation of a Neuronal Microcircuit in the CA1 Area of the Hippocampus Reveals Synaptic Dysfunction in Dravet Syndrome Mice

Almog

Mavashov

Brusel

et al. 2022

Front. Mol. Neurosci.

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Dravet syndrome is severe childhood-onset epilepsy, caused by loss of function mutations in the SCN1A gene, encoding for the voltage-gated sodium channel NaV1.1. The leading hypothesis is that Dravet is caused by selective reduction in the excitability of inhibitory neurons, due to hampered activity of NaV1.1 channels in these cells. However, these initial neuronal changes can lead to further network alterations. Here, focusing on the CA1 microcircuit in hippocampal brain slices of Dravet syndrome (DS, Scn1aA1783V/WT) and wild-type (WT) mice, we examined the functional response to the application of Hm1a, a specific NaV1.1 activator, in CA1 stratum-oriens (SO) interneurons and CA1 pyramidal excitatory neurons. DS SO interneurons demonstrated reduced firing and depolarized threshold for action potential (AP), indicating impaired activity. Nevertheless, Hm1a induced a similar AP threshold hyperpolarization in WT and DS interneurons. Conversely, a smaller effect of Hm1a was observed in CA1 pyramidal neurons of DS mice. In these excitatory cells, Hm1a application resulted in WT-specific AP threshold hyperpolarization and increased firing probability, with no effect on DS neurons. Additionally, when the firing of SO interneurons was triggered by CA3 stimulation and relayed via activation of CA1 excitatory neurons, the firing probability was similar in WT and DS interneurons, also featuring a comparable increase in the firing probability following Hm1a application. Interestingly, a similar functional response to Hm1a was observed in a second DS mouse model, harboring the nonsense Scn1aR613X mutation. Furthermore, we show homeostatic synaptic alterations in both CA1 pyramidal neurons and SO interneurons, consistent with reduced excitation and inhibition onto CA1 pyramidal neurons and increased release probability in the CA1-SO synapse. Together, these results suggest global neuronal alterations within the CA1 microcircuit extending beyond the direct impact of NaV1.1 dysfunction.

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“…It is also known that plastic changes occur in brain circuits in response to pathogenic variants of disease-associated genes. Two recent papers show that the electrical excitability of Nav1.2-expressing excitatory neurons in striatum and neocortex is actually enhanced, rather than impaired, in mice lacking Scn2a (21,22), due to complex interactions between and compensatory reorganization of Na + and potassium (K + ) currents. What changes might occur during development in Scn2a encephalopathy remains unknown.…”

Section: Considering Safety and Efficacymentioning

confidence: 99%

All our knowledge begins with the antisenses

Goldberg¹

2021

Journal of Clinical Investigation

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Paradoxical hyperexcitability from NaV1.2 sodium channel loss in neocortical pyramidal cells

Cited by 60 publications

References 52 publications

Pharmacological Inhibition of Wee1 Kinase Selectively Modulates the Voltage-Gated Na+ Channel 1.2 Macromolecular Complex

Pharmacological Inhibition of Wee1 Kinase Selectively Modulates the Voltage-Gated Na+ Channel 1.2 Macromolecular Complex

Functional Investigation of a Neuronal Microcircuit in the CA1 Area of the Hippocampus Reveals Synaptic Dysfunction in Dravet Syndrome Mice

All our knowledge begins with the antisenses

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