Dataset Information

Ca_V 3.2 drives sustained burst-firing, which is critical for absence seizure propagation in reticular thalamic neurons.

ABSTRACT:

Objective

Genetic alterations have been identified in the CACNA1H gene, encoding the Ca_V 3.2 T-type calcium channel in patients with absence epilepsy, yet the precise mechanisms relating to seizure propagation and spike-wave-discharge (SWD) pacemaking remain unknown. Neurons of the thalamic reticular nucleus (TRN) express high levels of Ca_V 3.2 calcium channels, and we investigated whether a gain-of-function mutation in the Cacna1h gene in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) contributes to seizure propagation and pacemaking in the TRN.

Methods

Pathophysiological contributions of Ca_V 3.2 calcium channels to burst firing and absence seizures were assessed in vitro using acute brain slice electrophysiology and quantitative real-time polymerase chain reaction (PCR) and in vivo using free-moving electrocorticography recordings.

Results

TRN neurons from GAERS display sustained oscillatory burst-firing that is both age- and frequency-dependent, occurring only in the frequencies overlapping with GAERS SWDs and correlating with the expression of a Ca_V 3.2 mutation-sensitive splice variant. In vivo knock-down of Ca_V 3.2 using direct thalamic injection of lipid nanoparticles containing Ca_V 3.2 dicer small interfering (Dsi) RNA normalized TRN burst-firing, and in free-moving GAERS significantly shortened seizures.

Significance

This supports a role for TRN Ca_V 3.2 T-type channels in propagating thalamocortical network seizures and setting the pacemaking frequency of SWDs.

SUBMITTER: Cain SM

PROVIDER: S-EPMC5900875 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Publications

Ca<sub>V</sub> 3.2 drives sustained burst-firing, which is critical for absence seizure propagation in reticular thalamic neurons.

Cain Stuart M SM Tyson John R JR Choi Hyun-Beom HB Ko Rebecca R Lin Paulo J C PJC LeDue Jeffrey M JM Powell Kim L KL Bernier Louis-Philippe LP Rungta Ravi L RL Yang Yi Y Cullis Pieter R PR O'Brien Terence J TJ MacVicar Brian A BA Snutch Terrance P TP

Epilepsia 20180221 4

<h4>Objective</h4>Genetic alterations have been identified in the CACNA1H gene, encoding the Ca<sub>V</sub> 3.2 T-type calcium channel in patients with absence epilepsy, yet the precise mechanisms relating to seizure propagation and spike-wave-discharge (SWD) pacemaking remain unknown. Neurons of the thalamic reticular nucleus (TRN) express high levels of Ca<sub>V</sub> 3.2 calcium channels, and we investigated whether a gain-of-function mutation in the Cacna1h gene in Genetic Absence Epilepsy R ...[more]

PMID: 29468672

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Project description:Chronic refractory central post-stroke pain (CPSP), one of the most disabling consequences of cerebral stroke, occurs in up to 10% of patients with CPSP. Because a considerable proportion of these patients with chronic pain remain resistant to pharmacological and behavioral therapies, adjunctive invasive and non-invasive brain stimulation therapies are needed. We performed a review of human studies applying burst and conventional motor cortex stimulation (burstMCS and cMCS, respectively) for chronic pain states, on the basis of data sources identified through searches of PubMed, MEDLINE/OVID, and SCOPUS, as well as manual searches of the bibliographies of known primary and review articles. Our aim was to review and discuss clinical data on the indications of burstMCS for various chronic pain states originating from central stroke (excluding trigeminal facial pain). In addition, we assessed the efficacy and safety of burst versus cMCS for central post-stroke pain with an extended follow-up of 5 years in a 60-year-old man. According to our review, uncontrolled observational human cohort studies and one RCT using cMCS waveforms have revealed a meaningful clinical response; however, these studies lacked placebo groups and extended observation periods. In our case report, we found that 3 months of adjunctive cMCS reduced pain levels [visual analog scale (VAS) pre: 9/10 versus VAS post 7/10], whereas the pain decreased further under burstMCS (VAS pre: 7/10 versus VAS post: 2/10); the study involved a follow-up of 5 years and the following parameters: burst rate 40 Hz (500 Hz), 1-1.75 mA, 1 ms, bipolar configuration. To date, only limited evidence exists for the efficacy and safety of burst motor cortex stimulation for the treatment of refractory chronic pain. BurstMCS resulted in significantly decreased post-stroke pain observed after 5 years of cMCS. The available literature suggests similar efficacy as that of conventional (tonic) motor cortex stimulation, although the results are preliminary. Mechanistically, the precise mechanism of action is not fully understood. However, burstMCS may interact with the nociceptive thalamic-cingulate and descending spinal pain networks. To determine the potential utility of this treatment, large-scale sham-controlled trials comparing cMCS and burstMCS are highly recommended.

Dataset Information

Ca_V 3.2 drives sustained burst-firing, which is critical for absence seizure propagation in reticular thalamic neurons.

Objective

Methods

Results

Significance

Publications

Ca<sub>V</sub> 3.2 drives sustained burst-firing, which is critical for absence seizure propagation in reticular thalamic neurons.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

CaV 3.2 drives sustained burst-firing, which is critical for absence seizure propagation in reticular thalamic neurons.

Objective

Methods

Results

Significance

Publications

Ca<sub>V</sub> 3.2 drives sustained burst-firing, which is critical for absence seizure propagation in reticular thalamic neurons.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Ca_V 3.2 drives sustained burst-firing, which is critical for absence seizure propagation in reticular thalamic neurons.