Synergistic positive feedback underlying seizure initiation

Rt, Graham; Parrish, R. Ryley; Alberio, Laura; El, Johnson; Lj, Owens; Aj, Trevelyan

doi:10.1101/2021.02.28.433224

Cited by 12 publications

(18 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additionally, while our pyramidal cell intrinsic excitability study assays axonal initial segment (AIS) and somatic excitability, seizure like-events are network level events, where dendrites, axons, and postsynaptic release of neurotransmitters are also critical components of seizure propagation. For example, dendritic plateauing has been shown to be necessary for seizure generation, suggesting important network changes required for this type of pathological activity ( Graham et al, 2021 ). Furthermore, axonal propagation of action potentials in neurons has been demonstrated to be more sensitive to sodium channel block than somatic action potentials ( Hu and Jonas, 2014 ; Kaneko et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological determination of the fractional block of Nav channels required to impair neuronal excitability and ex vivo seizures

Thouta

Waldbrook

Lin

et al. 2022

Front. Cell. Neurosci.

Self Cite

View full text Add to dashboard Cite

Voltage-gated sodium channels (Nav) are essential for the initiation and propagation of action potentials in neurons. Of the nine human channel subtypes, Nav1.1, Nav1.2 and Nav1.6 are prominently expressed in the adult central nervous system (CNS). All three of these sodium channel subtypes are sensitive to block by the neurotoxin tetrodotoxin (TTX), with TTX being almost equipotent on all three subtypes. In the present study we have used TTX to determine the fractional block of Nav channels required to impair action potential firing in pyramidal neurons and reduce network seizure-like activity. Using automated patch-clamp electrophysiology, we first determined the IC50s of TTX on mouse Nav1.1, Nav1.2 and Nav1.6 channels expressed in HEK cells, demonstrating this to be consistent with previously published data on human orthologs. We then compared this data to the potency of block of Nav current measured in pyramidal neurons from neocortical brain slices. Interestingly, we found that it requires nearly 10-fold greater concentration of TTX over the IC50 to induce significant block of action potentials using a current-step protocol. In contrast, concentrations near the IC50 resulted in a significant reduction in AP firing and increase in rheobase using a ramp protocol. Surprisingly, a 20% reduction in action potential generation observed with 3 nM TTX resulted in significant block of seizure-like activity in the 0 Mg2+ model of epilepsy. Additionally, we found that approximately 50% block in pyramidal cell intrinsic excitability is sufficient to completely block all seizure-like events. Furthermore, we also show that the anticonvulsant drug phenytoin blocked seizure-like events in a manner similar to TTX. These data serve as a critical starting point in understanding how fractional block of Nav channels affect intrinsic neuronal excitability and seizure-like activity. It further suggests that seizures can be controlled without significantly compromising intrinsic neuronal activity and determines the required fold over IC50 for novel and clinically relevant Nav channel blockers to produce efficacy and limit side effects.

show abstract

Section: Discussionmentioning

confidence: 99%

Pharmacological determination of the fractional block of Nav channels required to impair neuronal excitability and ex vivo seizures

Thouta

Waldbrook

Lin

et al. 2022

Front. Cell. Neurosci.

Self Cite

View full text Add to dashboard Cite

show abstract

“…In contrast, the intense GABAergic discharges seen in wild-type brain slices, while serving a protective purpose also has the unwanted consequence of loading their postsynaptic target cells with chloride ( 45 ), thereby contributing to the pathological evolution of activity ( 41 – 43 , 46 – 49 ). This is an example of positive feedback, where raised network activity creates the substrate that facilitates further neuronal activation that may be critical for seizure initiation ( 50 ).…”

Section: Discussionmentioning

confidence: 99%

PV-specific loss of the transcriptional coactivator PGC-1α slows down the evolution of epileptic activity in an acute ictogenic model

Scott

Parrish

Walsh

et al. 2022

Journal of Neurophysiology

Self Cite

View full text Add to dashboard Cite

The transcriptional coactivator, PGC-1α (peroxisome proliferator activated receptor gamma coactivator 1α), plays a key role coordinating energy requirement within cells. Its importance is reflected in the growing number of psychiatric and neurological conditions that have been associated with reduced PGC-1α levels. In cortical networks, PGC-1α is required for the induction of parvalbumin (PV) expression in interneurons, and PGC-1a deficiency affects synchronous GABAergic release. It is unknown, however, how this affects cortical excitability. We show here that knocking down PGC-1α specifically in the PV-expressing cells (PGC-1αPV-/-) blocks the activity-dependent regulation of the synaptic proteins, SYT2 and CPLX1. More surprisingly, this cell-class specific knock-out of PGC-1α appears to have a novel anti-epileptic effect, as assayed in brain slices bathed in 0 Mg2+ media. The rate of occurrence of pre-ictal discharges developed approximately equivalently in wild-type and PGC-1αPV-/- brain slices, but the intensity of these discharges was lower in PGC-1αPV-/- slices, as evident from the reduced power in the gamma range and reduced firing rates in both PV interneurons and pyramidal cells during these discharges. Reflecting this reduced intensity in the pre-ictal discharges, the PGC-1αPV-/- brain slices experienced many more discharges before transitioning into a seizure-like event. Consequently, there was a large increase in the latency to the first seizure-like event in brain slices lacking PGC-1α in PV interneurons. We conclude that knocking down PGC-1α limits the range of PV interneuron firing, and this slows the pathophysiological escalation during ictogenesis.

show abstract

“…Additionally, while our pyramidal cell intrinsic excitability study assays axonal initial segment (AIS) and somatic excitability, seizure like-events are network level events, where dendrites, axons, and postsynaptic release of neurotransmitters are also critical components of seizure propagation. For example, dendritic plateauing has been shown to be necessary for seizure generation, suggesting important network changes required for this type of pathological activity (Graham et al, 2021). Furthermore, axonal propagation of action potentials in neurons has been demonstrated to be more sensitive to sodium channel block than somatic action potentials (Kaneko et al, 2022, Hu and Jonas, 2014).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological determination of the fractional block of Nav channels required to impair neuronal excitability and ex vivo seizures

Thouta

Waldbrook

Lin

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Voltage-gated sodium channels (Nav) are essential for the initiation and propagation of action potentials in neurons. Of the different channel subtypes, Nav1.1, Nav1.2 and Nav1.6 are prominently expressed in the adult central nervous system (CNS). All three of these sodium channel subtypes are sensitive to block by the neurotoxin tetrodotoxin (TTX), with TTX being almost equipotent on all three subtypes. In the present study we have used TTX to determine the fractional block of Nav channels required to impair action potential firing in pyramidal neurons and reduce network seizure-like activity. Using automated patch-clamp electrophysiology, we first determined the IC50s of TTX on mouse Nav1.1, Nav1.2 and Nav1.6 channels expressed in HEK cells, demonstrating this to be consistent with previously published data on human Nav channels. We then compared this data to the potency of block of Nav current measured in pyramidal neurons from neocortical brain slices. Interestingly, we found that it requires nearly 10-fold greater concentration of TTX over the IC50 to induce significant block of action potentials using a current-step protocol. In contrast, concentrations near the IC50 resulted in a significant reduction in AP firing and increase in rheobase using a ramp protocol. Surprisingly, a 20% reduction in action potential generation observed with 3 nM TTX resulted in significant block of seizure-like activity in the 0 Mg2+ model of epilepsy. Additionally, we found that approximately 50% block in pyramidal cell intrinsic excitability is sufficient to completely block all seizure-like events. These data serve as a critical starting point in understanding how fractional block of Nav channels affect intrinsic neuronal excitability and seizure-like activity. It further suggests that seizures can be controlled without significantly compromising intrinsic neuronal activity and determines the required fold over IC50 for novel and clinically relevant Nav channel blockers to produce efficacy and limit side effects.

show abstract

Synergistic positive feedback underlying seizure initiation

Cited by 12 publications

References 57 publications

Pharmacological determination of the fractional block of Nav channels required to impair neuronal excitability and ex vivo seizures

Pharmacological determination of the fractional block of Nav channels required to impair neuronal excitability and ex vivo seizures

PV-specific loss of the transcriptional coactivator PGC-1α slows down the evolution of epileptic activity in an acute ictogenic model

Pharmacological determination of the fractional block of Nav channels required to impair neuronal excitability and ex vivo seizures

Contact Info

Product

Resources

About