CaV3.2 drives sustained burst‐firing, which is critical for absence seizure propagation in reticular thalamic neurons

Cain, Stuart M.; Tyson, John R.; Choi, Hyun B.; Ko, Rebecca W.Y.; Lin, Paulo J.C.; LeDue, Jeffrey; Powell, Kim L.; Bernier, Louis Philippe; Rungta, Ravi L.; Yang, Yi; Cullis, Pieter R.; O’Brien, Terence J.; MacVicar, Brian A.; Snutch, Terrance P.

doi:10.1111/epi.14018

Cited by 42 publications

(55 citation statements)

References 41 publications

(111 reference statements)

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“…However, in GAERS, a different rat strain with genetic absence epilepsy, a change in the gene CACNA1H increased the Ca V 3.2 current in nRT [24]. These results indicate that the T-type calcium channel blockers applied to the cortex or nRT can effect SWD expression in GAERS [25]. In our study, systemic and i.c.v.…”

Section: Discussion/conclusionsupporting

confidence: 45%

Effect of U-92032, T-Type Ca2+ Channel Blocker, on Rats with Genetic Absence Epilepsy

et al. 2020

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Introduction: Absence epilepsy is associated with diffuse spike-and-wave discharges (SWD) on the electroencephalogram (EEG). Recent studies have demonstrated that the primary somatosensory cortex is also implicated in the generation of the SWDs. Objective: This study investigated the effects of systemic and local administrations of U-92032 into the brain of Genetic Absence Epilepsy Rats from Strasbourg (GAERS). Methods: GAERS animals underwent stereotaxic surgery for the placement of EEG recording electrodes and guide cannulas for U-92032 administration into the lateral ventricle (intracerebroventricular [i.c.v.]), upper lips area (S1Ulp) or barrel field area (S1B) of primary somatosensory cortex. Following 7 days of recovery, electrical activity was recorded continuously for 1 h before and 6 h after intraperitoneal (0.25; 1; 5 mg/kg i.p.) or local U-92032 or dimethyl sulfoxide (DMSO) injections. Results: No changes were detected in the cumulative duration, mean duration, and number of SWDs following i.p. U-92032 injections. Local i.c.v. injections of U-92032 caused a significant decrease in the cumulative duration (i.c.v., 50 and 100 nmol/L), mean duration (i.c.v., 50, 100, and 250 nmol/L), and the number (i.c.v., 250 nmol/L) of SWDs compared to DMSO groups. Intra-cortical (S1Ulp and S1B) U-92032 injections caused a significant decrease in all 3 parameters compared to DMSO groups, as well. Conclusion: Intra-cortical injection of U-92032 caused almost complete removal of SWDs in GAERS and i.c.v. administration resulted in a significant reduction. However, systemic i.p. administration did not cause a significant change with the applied doses.

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Section: Discussion/conclusionsupporting

confidence: 45%

Effect of U-92032, T-Type Ca2+ Channel Blocker, on Rats with Genetic Absence Epilepsy

et al. 2020

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“…It is well established that SWDs result from hypersynchronized oscillations in the corticothalamo-cortical networks. These oscillations were commonly thought to originate from sustained burst firing of thalamic neurons (Danober et al, 1998;Huguenard and McCormick, 2007), underlain by increased Ca 2+ currents through T-type voltage-gated calcium channels (Cain and Snutch, 2013;Cain et al, 2018;Cheong and Shin, 2013). However, there is compelling evidence for a focal origin in specific regions of the somatosensory cortex (McCafferty et al, 2018;Meeren et al, 2002;Polack et al, 2007;Zheng et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

G protein-coupled potassium channels implicated in mouse and cellular models of GNB1 Encephalopathy

Colombo

Petri

Shalomov

et al. 2019

Preprint

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De novo mutations in GNB1, encoding the Gβ1 subunit of G proteins, cause a neurodevelopmental disorder with global developmental delay and epilepsy. Mice carrying a pathogenic mutation, K78R, recapitulate aspects of the disorder, including developmental delay and frequent spike-wave discharges (SWD). Cultured mutant cortical neurons display aberrant bursting activity on multi-electrode arrays. Strikingly, the antiepileptic drug ethosuximide (ETX) restores normal neuronal network behavior in vitro and suppresses SWD in vivo. In contrast, while valproic acid suppresses SWD, it does not restore normal network behavior, suggesting that ETX has mechanistic specificity for the effects of aberrant Gβ1 signaling. Consistent with this, we show that K78R is a gain-of-function of G protein-coupled potassium channel (GIRK) activation that is potently inhibited by ETX. This work suggests that altered Gβ1 signaling causes disease in part through effects on GIRK channels, illustrates the utility of cultured neuronal networks in pharmacological screening, and establishes effective pre-clinical models for GNB1 Encephalopathy.

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“…T-type Ca 2+ channels (T-channels) can be activated by small depolarizations of the plasma membrane and have been implicated in a variety of physiological processes, including fertilization, neuronal firing, cancer therapy, hormone secretion and muscle fiber development [8][9][10][11][12] . Bijlenga 13 .…”

Section: Introductionmentioning

confidence: 99%

CACNA1H downregulation induces skeletal muscle atrophy involving endoplasmic reticulum stress activation and autophagy flux blockade

Hao

et al. 2020

Cell Death Dis

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Multiple vaginal delivery (MVD) is an important factor for pelvic floor muscle (PFM) function decline and pelvic floor dysfunction (PFD). PFD is common in middle-aged and elderly women, but its pathogenesis is not clear. In this study, we found that the expression of CACNA1H was lower in the PFM of old mice after MVD compared with old or adult mice. In in-vitro studies, we found that treatment with the T-type Ca 2+ channel (T-channel) inhibitor NNC-55 or downregulation of the CACNA1H gene by siRNA intervention promoted myotube atrophy and apoptosis. Mechanistically, we revealed that NNC-55 increased the expression of GRP78 and DDIT3 in myotubes, indicating endoplasmic reticulum stress (ERS) activation, and that the IRE1 and PERK pathways might be involved in this effect. NNC-55 induced the formation of autophagosomes but inhibited autophagy flux. Moreover, rapamycin, an autophagy activator, did not rescue myotube atrophy or apoptosis induced by NNC-55, and the autophagy inhibitors 3-MA and HCQ accelerated this damage. Further studies showed that the ERS inhibitors 4-PBA and TUDAC relieved NNC-55-induced damage and autophagy flux blockade. Finally, we found multisite muscle atrophy and decreased muscle function in Cacna1h −/− (TH-null) mice, as well as increased autophagy inhibition and apoptotic signals in the PFM of old WT mice after MVD and TH-null mice. Taken together, our results suggest that MVD-associated PFD is partially attributed to CACNA1H downregulation-induced PFM atrophy and that ERS is a potential therapeutic target for this disease.

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Ca_V3.2 drives sustained burst‐firing, which is critical for absence seizure propagation in reticular thalamic neurons

Cited by 42 publications

References 41 publications

Effect of U-92032, T-Type Ca<sup>2+</sup> Channel Blocker, on Rats with Genetic Absence Epilepsy

Effect of U-92032, T-Type Ca<sup>2+</sup> Channel Blocker, on Rats with Genetic Absence Epilepsy

G protein-coupled potassium channels implicated in mouse and cellular models of GNB1 Encephalopathy

CACNA1H downregulation induces skeletal muscle atrophy involving endoplasmic reticulum stress activation and autophagy flux blockade

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