CaV2.3 Channels Are Critical for Oscillatory Burst Discharges in the Reticular Thalamus and Absence Epilepsy

Zaman, Tariq; Lee, Kyoobin; Park, Cheongdahm; Paydar, Afshin; Choi, Jee Hyun; Cheong, Eunji; Lee, C. Justin; Shin, Hee Sup

doi:10.1016/j.neuron.2011.02.042

Cited by 82 publications

(77 citation statements)

References 63 publications

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“…Studies in animal models have implicated cortical hyperexcitability and unbalanced excitation/inhibition in the thalamic network, which is consistent with the activity observed in these regions during seizure attacks in humans [110]. Several genetic mouse lines with alterations of nRt excitability represent a good model to test therapeutic interventions for absence epilepsy [9,24,26,27].…”

Section: Sleep Spindles In Pathologymentioning

confidence: 60%

“…Foremost amongst the ionic mechanisms underlying rhythmic nRt bursting are the low-voltage gated T-type Ca 2+ channels (T channels) and the small-conductance Ca 2+ -activated type-2 K + channel (SK2 or Kcnn2 channel). Bursting is additionally shaped by voltage-dependent K + channels [8], R-type channels [9], sarco/endoplasmic reticulum Ca 2+ -ATPases [10], and Ca 2+ -induced Ca 2+ release via ryanodine receptors [11]. However, genetic manipulations of T channels and SK2 channels have proven particularly useful in selectively modifying sleep spindles [12,13].…”

Section: Novel Molecular Aspects Of Spindle Generationmentioning

confidence: 99%

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Manipulating sleep spindles – expanding views on sleep, memory, and disease

Astori

Wimmer²,

Lüthi³

2013

Trends in Neurosciences

127

113

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Abstract:Sleep spindles are distinctive electroencephalographic (EEG) oscillations emerging during non-rapid-eye-movement sleep (NREMS) that have been implicated in multiple brain functions, including sleep quality, sensory gating, learning and memory. Despite considerable knowledge about the mechanisms underlying these neuronal rhythms, their function remains poorly understood and current views are largely based on correlational evidence. Here, we review recent studies in humans and rodents that have begun to broaden our understanding of the role of spindles in the normal and disordered brain. We show that newly identified molecular substrates of spindle oscillations, in combination with evolving technological progress, offer novel targets and tools to selectively manipulate spindles and dissect their role in sleep-dependent processes. Powered by Editorial Manager® and ProduXion Manager® from Aries Systems CorporationAstori et al. Highlights Newly recognized ion channel subtypes generating spindle rhythms are described. The contribution of spindles to arousal threshold and sleep quality is discussed. The proposed role of spindles in memory consolidation is examined. A function of thalamic spindles in neural development is suggested. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 4 Previous excellent reviews have thoroughly described cellular and network bases of spindle generation [3,6,7]. Here, we first review recent work on genetic models that has expanded the mechanistic understanding of this EEG rhythm through the modification of novel molecular substrates. We then discuss the current views about the functional aspects of spindles in brain physiology and pathology, as obtained from studies in naturally sleeping animals and humans. We highlight studies indicating that spindles are accessible for selective interventions, and that, with emerging technologies, will open avenues to decipher spindle function. Novel molecular aspects of spindle generationSleep spindles emerge from a limited set of cellular participants: the resonating core of these waxing-and-waning oscillations resides in the nRt-TC loop, which sustains repetitive burst discharges of its cellular components under the control of cortical inputs (Figure 1 Another important factor in the generation and maintenance of reticular intrinsic oscillations is the aforementioned SK2 or Kcnn2 channel. The vigorous Ca 2+ influx in nRt dendrites originating from Ca V 3.3 channels gates SK2 channels, thereby creating a burstafterhyperpolarization (bAHP) [12,19]. As T channels recover partially from inactivation duri...

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Section: Sleep Spindles In Pathologymentioning

confidence: 60%

Section: Novel Molecular Aspects Of Spindle Generationmentioning

confidence: 99%

Manipulating sleep spindles – expanding views on sleep, memory, and disease

Astori

Wimmer²,

Lüthi³

2013

Trends in Neurosciences

127

113

View full text Add to dashboard Cite

show abstract

“…The roles, if any, played by other calcium channel subtypes in epileptogenesis await elucidation. Ca V 2.3 (R-type) channels in the thalamus have been implicated in burst firing and potentially proictogenic "plateau potentials" (Randall and Tsien 1997;Metz et al 2005;Zaman et al 2011) with Ca V 2.3 null mice showing an altered susceptibility to absence seizures, as well as resistance to pharmacologically induced limbic seizures, convulsions, and excitotoxic cell death (Weiergraber et al 2006(Weiergraber et al , 2007(Weiergraber et al , 2008, tantalizing data that require further study.…”

Section: Discussionmentioning

confidence: 99%

The Role of Calcium Channels in Epilepsy

Rajakulendran

Hanna

2016

Cold Spring Harb Perspect Med

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A central theme in the quest to unravel the genetic basis of epilepsy has been the effort to elucidate the roles played by inherited defects in ion channels. The ubiquitous expression of voltage-gated calcium channels (VGCCs) throughout the central nervous system (CNS), along with their involvement in fundamental processes, such as neuronal excitability and synaptic transmission, has made them attractive candidates. Recent insights provided by the identification of mutations in the P/Q-type calcium channel in humans and rodents with epilepsy and the finding of thalamic T-type calcium channel dysfunction in the absence of seizures have raised expectations of a causal role of calcium channels in the polygenic inheritance of idiopathic epilepsy. In this review, we consider how genetic variation in neuronal VGCCs may influence the development of epilepsy.

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“…Additionally, low-threshold Ca 2+ currents evoked in Ca V 3.3 −/− cells were invariant against the R-type channel blocker SNX-482 (change by −1.0 ± 2.9%; n = 4, P > 0.05) (Fig. S4) at doses that reduce R currents in nRt slices (20). Around resting membrane potentials, low-threshold Ca 2+ currents thus are carried dominantly by T channels in WT nRt cells and contain two components with different Ni 2+ sensitivity (13 (16).…”

Section: −/−mentioning

confidence: 95%

The Ca _V 3.3 calcium channel is the major sleep spindle pacemaker in thalamus

Astori

Wimmer

Prosser

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

184

220

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Low-threshold (T-type) Ca2+ channels encoded by the Ca V 3 genes endow neurons with oscillatory properties that underlie slow waves characteristic of the non-rapid eye movement (NREM) sleep EEG. Three Ca V 3 channel subtypes are expressed in the thalamocortical (TC) system, but their respective roles for the sleep EEG are unclear. Ca V 3.3 protein is expressed abundantly in the nucleus reticularis thalami (nRt), an essential oscillatory burst generator. We report the characterization of a transgenic Ca V 3.3 −/− mouse line and demonstrate that Ca V 3.3 channels are indispensable for nRt function and for sleep spindles, a hallmark of natural sleep. The absence of Ca V 3.3 channels prevented oscillatory bursting in the lowfrequency (4-10 Hz) range in nRt cells but spared tonic discharge. In contrast, adjacent TC neurons expressing Ca V 3.1 channels retained low-threshold bursts. Nevertheless, the generation of synchronized thalamic network oscillations underlying sleep-spindle waves was weakened markedly because of the reduced inhibition of TC neurons via nRt cells. T currents in Ca V 3.3 −/− mice were <30% compared with those in WT mice, and the remaining current, carried by Ca V 3.2 channels, generated dendritic [Ca 2+ ] i signals insufficient to provoke oscillatory bursting that arises from interplay with Ca 2+ -dependent small conductance-type 2 K + channels. Finally, naturally sleeping Ca V 3.3 −/− mice showed a selective reduction in the power density of the σ frequency band (10-12 Hz) at transitions from NREM to REM sleep, with other EEG waves remaining unaltered. Together, these data identify a central role for Ca V 3.3 channels in the rhythmogenic properties of the sleep-spindle generator and provide a molecular target to elucidate the roles of sleep spindles for brain function and development.2+ channels encoded by the Ca V 3 genes activate near resting membrane potentials and generate low-threshold Ca 2+ spikes leading to burst firing and low-frequency oscillatory discharge that are prominent in some thalamic, olivary, and cerebellar neurons (1). Among the low-threshold Ca 2+ currents carried by Ca V 3 channels, those mediated by Ca V 3.3 channels are unique in that they display the slowest time course, the fastest recovery from inactivation, and often the most depolarized activation voltages (2, 3). Moreover, Ca V 3.3 mRNA is expressed predominantly in brain and shows highest regional specificity (3-5). To date, identification of specific physiological roles for Ca V 3.3 channels has been hampered for several reasons. First, these channels typically are coexpressed with Ca V 3.1 and/or Ca V 3.2 channels (4, 5), and specific pharmacological tools are not available (1). Second, Ca V 3.3 channels often are found in distal dendrites, limiting accessibility for electrophysiological characterization (6, 7). Finally, Ca V 3.3 −/− mice have not been reported, whereas Ca V 3.1 −/− and Ca V 3.2 knockdown mice have helped address the roles of Ca V 3.1 and Ca V 3.2 channels in sleep and pain, respectively (8-10)...

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CaV2.3 Channels Are Critical for Oscillatory Burst Discharges in the Reticular Thalamus and Absence Epilepsy

Cited by 82 publications

References 63 publications

Manipulating sleep spindles – expanding views on sleep, memory, and disease

Manipulating sleep spindles – expanding views on sleep, memory, and disease

The Role of Calcium Channels in Epilepsy

The Ca _V 3.3 calcium channel is the major sleep spindle pacemaker in thalamus

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CaV2.3 Channels Are Critical for Oscillatory Burst Discharges in the Reticular Thalamus and Absence Epilepsy

Cited by 82 publications

References 63 publications

Manipulating sleep spindles – expanding views on sleep, memory, and disease

Manipulating sleep spindles – expanding views on sleep, memory, and disease

The Role of Calcium Channels in Epilepsy

The Ca V 3.3 calcium channel is the major sleep spindle pacemaker in thalamus

Contact Info

Product

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The Ca _V 3.3 calcium channel is the major sleep spindle pacemaker in thalamus