Respiratory alkalosis provokes spike-wave discharges in seizure-prone rats

Salvati, Kathryn A.; Souza, George M. P. R.; Lu, Adam C; Ritger, Matthew L; Guyenet, Patrice G.; Abbott, Stephen B.G.; Beenhakker, Mark P.

doi:10.7554/elife.72898

Cited by 15 publications

(11 citation statements)

References 109 publications

(136 reference statements)

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“…1 ). The pattern of this c-Fos expression in the BK-D434G MLT mirrors what was observed in another rodent model for absence seizures, the WAG/Rij rat, in which the seizures were triggered by hypoxia-induced hyperventilation 45 . These findings suggest that the role of the MLT in absence seizures is not limited to the context of the BK-D434G mutation.…”

Section: Discussionsupporting

confidence: 75%

Attenuating midline thalamus bursting to mitigate absence epilepsy

Dong,

Bakhurin,

et al. 2023

Preprint

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Advancing the mechanistic understanding of absence epilepsy is crucial for developing new therapeutics, especially for patients unresponsive to current treatments. Utilizing a recently developed mouse model of absence epilepsy carrying the BK gain-of-function channelopathy D434G, here we report that attenuating the burst firing of midline thalamus (MLT) neurons effectively prevents absence seizures. We found that enhanced BK channel activity in the BK-D434G MLT neurons promotes synchronized bursting during the ictal phase of absence seizures. Modulating MLT neurons through pharmacological reagents, optogenetic stimulation, or deep brain stimulation effectively attenuates burst firing, leading to reduced absence seizure frequency and increased vigilance. Additionally, enhancing vigilance by amphetamine, a stimulant medication, or physical perturbation also effectively suppresses MLT bursting and prevents absence seizures. These findings suggest that the MLT is a promising target for clinical interventions. Our diverse approaches offer valuable insights for developing new therapeutics to treat absence epilepsy.

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Section: Discussionsupporting

confidence: 75%

Attenuating midline thalamus bursting to mitigate absence epilepsy

Dong,

Bakhurin,

et al. 2023

Preprint

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“…Another way of alpha2-mediated upregulation of HCN channels is cellular alkalinization [ 132 ] which shifts I h activation potential to more depolarized values [ 133 ]. A recent study showed that in rats genetically predisposed to absence epilepsy, spike-wave activity can be triggered by hypoxia-induced blood alkalosis resulting in the activation of neurons in the intralaminar thalamic nuclei [ 134 ].…”

Section: Cellular Targets Of Alpha2 Ars In Relation To Spike-wave Act...mentioning

confidence: 99%

Alpha2-Adrenergic Receptors as a Pharmacological Target for Spike-Wave Epilepsy

Sitnikova

Rutskova

Smirnov

2023

IJMS

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Spike-wave discharges are the hallmark of idiopathic generalized epilepsy. They are caused by a disorder in the thalamocortical network. Commercially available anti-epileptic drugs have pronounced side effects (i.e., sedation and gastroenterological concerns), which might result from a low selectivity to molecular targets. We suggest a specific subtype of adrenergic receptors (ARs) as a promising anti-epileptic molecular target. In rats with a predisposition to absence epilepsy, alpha2 ARs agonists provoke sedation and enhance spike-wave activity during transitions from awake/sedation. A number of studies together with our own observations bring evidence that the sedative and proepileptic effects require different alpha2 ARs subtypes activation. Here we introduce a new concept on target pharmacotherapy of absence epilepsy via alpha2B ARs which are presented almost exclusively in the thalamus. We discuss HCN and calcium channels as the most relevant cellular targets of alpha2 ARs involved in spike-wave activity generation.

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“…The phase and depth of respiration has a well-established connection to epilepsy [27][28][29] , in contrast to other physiological brain pulsations 28 . In routine EEG diagnostics, hyperventilation reduces epileptic seizure threshold and increases neuronal excitability, and is thus routinely used to provoke seizure activity during recording session in patients with epilepsy, even though the underlying mechanisms remain unknown 56 . The increased power of respiratory brain pulsations detected in epileptic brains may similarly affect the CSF solute transport, alter neuronal excitability thus lowering the seizure threshold 28 , especially given the tendency for both slower and reversed impulse propagation (Figs.…”

Section: Discussionmentioning

confidence: 99%

Respiratory brain impulse propagation in focal epilepsy

Elabasy

Suhonen

Rajna

et al. 2023

Sci Rep

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Respiratory brain pulsations pertaining to intra-axial hydrodynamic solute transport are markedly altered in focal epilepsy. We used optical flow analysis of ultra-fast functional magnetic resonance imaging (fMRI) data to investigate the velocity characteristics of respiratory brain impulse propagation in patients with focal epilepsy treated with antiseizure medication (ASM) (medicated patients with focal epilepsy; ME, n = 23), drug-naïve patients with at least one seizure (DN, n = 19) and matched healthy control subjects (HC, n = 75). We detected in the two patient groups (ME and DN) several significant alterations in the respiratory brain pulsation propagation velocity, which showed a bidirectional change dominated by a reduction in speed. Furthermore, the respiratory impulses moved more in reversed or incoherent directions in both patient groups vs. the HC group. The speed reductions and directionality changes occurred in specific phases of the respiratory cycle. In conclusion, irrespective of medication status, both patient groups showed incoherent and slower respiratory brain impulses, which may contribute to epileptic brain pathology by hindering brain hydrodynamics.

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Respiratory alkalosis provokes spike-wave discharges in seizure-prone rats

Cited by 15 publications

References 109 publications

Attenuating midline thalamus bursting to mitigate absence epilepsy

Attenuating midline thalamus bursting to mitigate absence epilepsy

Alpha2-Adrenergic Receptors as a Pharmacological Target for Spike-Wave Epilepsy

Respiratory brain impulse propagation in focal epilepsy

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