Downregulation of Spermine Augments Dendritic Persistent Sodium Currents and Synaptic Integration after Status Epilepticus

Royeck, Michel; Kelly, T.; Opitz, Thoralf; Otte, David-Marian; Rennhack, Andreas; Woitecki, Anne; Pitsch, Julika; Becker, Albert; Schoch, Susanne; Kaupp, U. Benjamin; Yaari, Yoel; Zimmer, Andreas; Beck, Hanno

doi:10.1523/jneurosci.0493-15.2015

Cited by 23 publications

(32 citation statements)

References 61 publications

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“…The transcriptome of human brain biopsies of pharmacoresistant focal epilepsy patients undergoing surgery for seizure control and of corresponding rodent models exhibits strong changes in the expression levels of a large number of genes compared with healthy hippocampus (Laurén et al, 2010;Okamoto et al, 2010;Hansen et al, 2014;Johnson et al, 2015). Many of these genes code for proteins with substantial impact on neuronal excitability, in particular distinct ion channels (Ellerkmann et al, 2003;Bernard et al, 2004;Royeck et al, 2015;van Loo et al, 2015;Gross et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Calcium Channel Subunit α2δ4 Is Regulated by Early Growth Response 1 and Facilitates Epileptogenesis

et al. 2019

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Transient brain insults, including status epilepticus (SE), can trigger a period of epileptogenesis during which functional and structural reorganization of neuronal networks occurs resulting in the onset of focal epileptic seizures. In recent years, mechanisms that regulate the dynamic transcription of individual genes during epileptogenesis and thereby contribute to the development of a hyperexcitable neuronal network have been elucidated. Our own results have shown early growth response 1 (Egr1) to transiently increase expression of the T-type voltage-dependent Ca 2ϩ channel (VDCC) subunit Ca V 3.2, a key proepileptogenic protein. However, epileptogenesis involves complex and dynamic transcriptomic alterations; and so far, our understanding of the transcriptional control mechanism of gene regulatory networks that act in the same processes is limited. Here, we have analyzed whether Egr1 acts as a key transcriptional regulator for genes contributing to the development of hyperexcitability during epileptogenesis. We found Egr1 to drive the expression of the VDCC subunit ␣2␦4, which was augmented early and persistently after pilocarpine-induced SE. Furthermore, we show that increasing levels of ␣2␦4 in the CA1 region of the hippocampus elevate seizure susceptibility of mice by slightly decreasing local network activity. Interestingly, we also detected increased expression levels of Egr1 and ␣2␦4 in human hippocampal biopsies obtained from epilepsy surgery. In conclusion, Egr1 controls the abundance of the VDCC subunits Ca V 3.2 and ␣2␦4, which act synergistically in epileptogenesis, and thereby contributes to a seizure-induced "transcriptional Ca 2ϩ channelopathy."

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Section: Introductionmentioning

confidence: 99%

Calcium Channel Subunit α2δ4 Is Regulated by Early Growth Response 1 and Facilitates Epileptogenesis

et al. 2019

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“…In CA1 neurons, a more dramatic increase in burst‐firing was observed following SE and attributed to increased persistent Na + currents ( I NaP ) and T‐type Ca 2+ channels in the dendrites . We did not systematically investigate the currents underlying burst‐firing in granule cells.…”

Section: Discussionmentioning

confidence: 99%

“…Two‐photon glutamate uncaging at dendrites of dentate granule cells was performed using a microscope equipped with a galvanometer‐based scanning system (Prairie Technologies) to photorelease 4‐Methoxy‐7‐nitroindolinyl‐caged‐L‐glutamate (MNI‐glutamate) (Biozol) at multiple dendritic spines. Multiphoton photorelease was obtained with an ultrafast, Ti:Sa‐pulsed laser (Chameleon Ultra, Coherent) tuned to 720–740 nm and targeted to individual spines . Action potential–induced [Ca 2+ ] i transients were recorded using Oregon green BAPTA (OGB‐1; 200 μ m ; Invitrogen) in linescan mode.…”

Section: Abbreviated Methods (For Full Methods See Data S1)mentioning

confidence: 99%

“…Multiphoton photorelease was obtained with an ultrafast, Ti:Sa-pulsed laser (Chameleon Ultra, Coherent) tuned to 720-740 nm and targeted to individual spines. 8,21,22 Action potential-induced [Ca 2+ ] i transients were recorded using Oregon green BAPTA (OGB-1; 200 lM; Invitrogen) in linescan mode.…”

Section: Abbreviated Methods (For Fullmentioning

confidence: 99%

“…18 In CA1 neurons, a more dramatic increase in burst-firing was observed following SE and attributed to increased persistent Na + currents (I NaP ) and T-type Ca 2+ channels in the dendrites. 22,24 We did not systematically investigate the currents underlying burst-firing in granule cells. Furthermore, we did not investigate dendritic properties using direct dendritic patch-clamp recordings, although the increased bAPevoked Ca 2+ transients in the proximal apical and basal dendrites of SE + HBD À and SE + HBD + cells indicate an enhanced dendritic electrogenesis that may contribute to burst-firing.…”

Section: Increased Burst-firing Outputmentioning

confidence: 99%

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Functional properties of granule cells with hilar basal dendrites in the epileptic dentate gyrus

Kelly

Beck

2016

Epilepsia

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SUMMARYObjective: The maturation of adult-born granule cells and their functional integration into the network is thought to play a key role in the proper functioning of the dentate gyrus. In temporal lobe epilepsy, adult-born granule cells in the dentate gyrus develop abnormally and possess a hilar basal dendrite (HBD). Although morphological studies have shown that these HBDs have synapses, little is known about the functional properties of these HBDs or the intrinsic and network properties of the granule cells that possess these aberrant dendrites. Methods: We performed patch-clamp recordings of granule cells within the granule cell layer "normotopic" from sham-control and status epilepticus (SE) animals. Normotopic granule cells from SE animals possessed an HBD (SE + HBD + cells) or not (SE + HBD À cells). Apical and basal dendrites were stimulated using multiphoton uncaging of glutamate. Two-photon Ca 2+ imaging was used to measure Ca 2+ transients associated with back-propagating action potentials (bAPs). Results: Near-synchronous synaptic input integrated linearly in apical dendrites from sham-control animals and was not significantly different in apical dendrites of SE + HBD À cells. The majority of HBDs integrated input linearly, similar to apical dendrites. However, 2 of 11 HBDs were capable of supralinear integration mediated by a dendritic spike. Furthermore, the bAP-evoked Ca 2+ transients were relatively well maintained along HBDs, compared with apical dendrites. This further suggests an enhanced electrogenesis in HBDs. In addition, the output of granule cells from epileptic tissue was enhanced, with both SE + HBD À and SE + HBD + cells displaying increased high-frequency (>100 Hz) burst-firing. Finally, both SE + HBD À and SE + HBD + cells received recurrent excitatory input that was capable of generating APs, especially in the absence of feedback inhibition. Significance: Taken together, these data suggest that the enhanced excitability of HBDs combined with the altered intrinsic and network properties of granule cells collude to promote excitability and synchrony in the epileptic dentate gyrus. KEY WORDS: Hippocampus, Dentate gyrus, Epilepsy, Patch-clamp, Granule cells, Adult born granule cells, Two-photon, Burst-firing, Neurogenesis, Dendrites, Neurons, Mossy fiber.The hippocampus is essential for episodic memory, 1,2 and the dentate gyrus is proposed to support memory formation by discriminating between similar events to create independent representations through pattern separation.3 Pattern separation involves the transformation of overlapping inputs into sparse independent representations. Sparse activity of the dentate gyrus is essential for this capability 4-6 and relies on unique properties of dentate granule cells, such as their specialized intrinsic properties and the strong

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How do we use in vitro models to understand epileptiform and ictal activity? A report of the TASK1‐WG4 group of the ILAE/AES Joint Translational Task Force

et al. 2018

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SummaryIn vitro brain tissue preparations allow the convenient and affordable study of brain networks and have allowed us to garner molecular, cellular, and electrophysiologic insights into brain function with a detail not achievable in vivo. Preparations from both rodent and human postsurgical tissue have been utilized to generate in vitro electrical activity similar to electrographic activity seen in patients with epilepsy. A great deal of knowledge about how brain networks generate various forms of epileptiform activity has been gained, but due to the multiple in vitro models and manipulations used, there is a need for a standardization across studies. Here, we describe epileptiform patterns generated using in vitro brain preparations, focusing on issues and best practices pertaining to recording, reporting, and interpretation of the electrophysiologic patterns observed. We also discuss criteria for defining in vitro seizure‐like patterns (i.e., ictal) and interictal discharges. Unifying terminologies and definitions are proposed. We suggest a set of best practices for reporting in vitro studies to favor both efficient across‐lab comparisons and translation to in vivo models and human studies.

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Downregulation of Spermine Augments Dendritic Persistent Sodium Currents and Synaptic Integration after Status Epilepticus

Cited by 23 publications

References 61 publications

Calcium Channel Subunit α2δ4 Is Regulated by Early Growth Response 1 and Facilitates Epileptogenesis

Calcium Channel Subunit α2δ4 Is Regulated by Early Growth Response 1 and Facilitates Epileptogenesis

Functional properties of granule cells with hilar basal dendrites in the epileptic dentate gyrus

How do we use in vitro models to understand epileptiform and ictal activity? A report of the TASK1‐WG4 group of the ILAE/AES Joint Translational Task Force

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