PURPOSE: Recently the Ca(v)2.3 (E/R-type) voltage-gated calcium channel (VGCC) has turned out to be not only a potential target for different antiepileptic drugs (e.g., lamotrigine, topiramate) but also a crucial component in the pathogenesis of absence epilepsy, human juvenile myoclonic epilepsy (JME), and epileptiform activity in CA1 neurons. The aim of our study was to perform an electroencephalographic analysis, seizure-susceptibility testing, and histomorphologic characterization of Ca(v)2.3-/- mice to unravel the functional relevance of Ca(v)2.3 in ictogenesis. METHODS: Generalized and brain-specific Ca(v)2.3 knockout animals were analyzed for spontaneous epileptiform discharges by using both electrocorticographic and deep intracerebral recordings. In addition, convulsive seizure activity was induced by systemic administration of either 4-aminopyridine (4-AP; 10 mg/kg, i.p.) or pentylenetetrazol (PTZ; 80 mg/kg, s.c.) to reveal possible alterations in seizure susceptibility. Besides histomorphologic analysis, expression studies of other voltage-gated Ca2+ channels in Ca(v)2.3-/- brains were carried out by using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Both electrocorticographic and deep intrahippocampal recordings exhibited no spontaneous epileptiform discharges indicative of convulsive or nonconvulsive seizure activity during long-term observation. Gross histology and expression levels of other voltage-gated Ca2+ channels remained unchanged in various brain regions. Surprisingly, PTZ-induced seizure susceptibility was dramatically reduced in Ca(v)2.3-deficient mice, whereas 4-AP sensitivity remained unchanged. CONCLUSIONS: Ca(v)2.3 ablation results in seizure resistance, strongly supporting recent findings in CA1 neurons that Ca(v)2.3 triggers epileptiform activity in specialized neurons via plateau potentials and afterdepolarizations. We provide novel insight into the functional involvement of Ca(v)2.3 in ictogenesis and seizure susceptibility on the whole-animal level.
PURPOSE: Recently the Ca(v)2.3 (E/R-type) voltage-gated calcium channel (VGCC) has turned out to be not only a potential target for different antiepileptic drugs (e.g., lamotrigine, topiramate) but also a crucial component in the pathogenesis of absence epilepsy, human juvenile myoclonic epilepsy (JME), and epileptiform activity in CA1 neurons. The aim of our study was to perform an electroencephalographic analysis, seizure-susceptibility testing, and histomorphologic characterization of Ca(v)2.3-/- mice to unravel the functional relevance of Ca(v)2.3 in ictogenesis. METHODS: Generalized and brain-specific Ca(v)2.3 knockout animals were analyzed for spontaneous epileptiform discharges by using both electrocorticographic and deep intracerebral recordings. In addition, convulsive seizure activity was induced by systemic administration of either 4-aminopyridine (4-AP; 10 mg/kg, i.p.) or pentylenetetrazol (PTZ; 80 mg/kg, s.c.) to reveal possible alterations in seizure susceptibility. Besides histomorphologic analysis, expression studies of other voltage-gated Ca2+ channels in Ca(v)2.3-/- brains were carried out by using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Both electrocorticographic and deep intrahippocampal recordings exhibited no spontaneous epileptiform discharges indicative of convulsive or nonconvulsive seizure activity during long-term observation. Gross histology and expression levels of other voltage-gated Ca2+ channels remained unchanged in various brain regions. Surprisingly, PTZ-induced seizure susceptibility was dramatically reduced in Ca(v)2.3-deficient mice, whereas 4-AP sensitivity remained unchanged. CONCLUSIONS:Ca(v)2.3 ablation results in seizure resistance, strongly supporting recent findings in CA1 neurons that Ca(v)2.3 triggers epileptiform activity in specialized neurons via plateau potentials and afterdepolarizations. We provide novel insight into the functional involvement of Ca(v)2.3 in ictogenesis and seizure susceptibility on the whole-animal level.
Authors: Erin E Gray; Jonathan G Murphy; Ying Liu; Ivan Trang; G Travis Tabor; Lin Lin; Dax A Hoffman Journal: J Neurosci Date: 2019-07-26 Impact factor: 6.167
Authors: Magdalena Elisabeth Siwek; Ralf Müller; Christina Henseler; Karl Broich; Anna Papazoglou; Marco Weiergräber Journal: Sleep Date: 2014-05-01 Impact factor: 5.849
Authors: Stephan E Lehnart; Marco Mongillo; Andrew Bellinger; Nicolas Lindegger; Bi-Xing Chen; William Hsueh; Steven Reiken; Anetta Wronska; Liam J Drew; Chris W Ward; W J Lederer; Robert S Kass; Gregory Morley; Andrew R Marks Journal: J Clin Invest Date: 2008-06 Impact factor: 14.808
Authors: Katherine L Helbig; Robert J Lauerer; Jacqueline C Bahr; Ivana A Souza; Candace T Myers; Betül Uysal; Niklas Schwarz; Maria A Gandini; Sun Huang; Boris Keren; Cyril Mignot; Alexandra Afenjar; Thierry Billette de Villemeur; Delphine Héron; Caroline Nava; Stéphanie Valence; Julien Buratti; Christina R Fagerberg; Kristina P Soerensen; Maria Kibaek; Erik-Jan Kamsteeg; David A Koolen; Boudewijn Gunning; H Jurgen Schelhaas; Michael C Kruer; Jordana Fox; Somayeh Bakhtiari; Randa Jarrar; Sergio Padilla-Lopez; Kristin Lindstrom; Sheng Chih Jin; Xue Zeng; Kaya Bilguvar; Antigone Papavasileiou; Qinghe Xing; Changlian Zhu; Katja Boysen; Filippo Vairo; Brendan C Lanpher; Eric W Klee; Jan-Mendelt Tillema; Eric T Payne; Margot A Cousin; Teresa M Kruisselbrink; Myra J Wick; Joshua Baker; Eric Haan; Nicholas Smith; Azita Sadeghpour; Erica E Davis; Nicholas Katsanis; Mark A Corbett; Alastair H MacLennan; Jozef Gecz; Saskia Biskup; Eva Goldmann; Lance H Rodan; Elizabeth Kichula; Eric Segal; Kelly E Jackson; Alexander Asamoah; David Dimmock; Julie McCarrier; Lorenzo D Botto; Francis Filloux; Tatiana Tvrdik; Gregory D Cascino; Sherry Klingerman; Catherine Neumann; Raymond Wang; Jessie C Jacobsen; Melinda A Nolan; Russell G Snell; Klaus Lehnert; Lynette G Sadleir; Britt-Marie Anderlid; Malin Kvarnung; Renzo Guerrini; Michael J Friez; Michael J Lyons; Jennifer Leonhard; Gabriel Kringlen; Kari Casas; Christelle M El Achkar; Lacey A Smith; Alexander Rotenberg; Annapurna Poduri; Alba Sanchis-Juan; Keren J Carss; Julia Rankin; Adam Zeman; F Lucy Raymond; Moira Blyth; Bronwyn Kerr; Karla Ruiz; Jill Urquhart; Imelda Hughes; Siddharth Banka; Ulrike B S Hedrich; Ingrid E Scheffer; Ingo Helbig; Gerald W Zamponi; Holger Lerche; Heather C Mefford Journal: Am J Hum Genet Date: 2018-10-18 Impact factor: 11.025