Hsin-Yi Kao1, Shuntong Hu1,2, Temenuzhka Mihaylova1, Julie Ziobro3, EunSeon Ahn4, Carli Fine4, David Brang4, Brendon O Watson5,6, Yu Wang1. 1. Department of Neurology, University of Michigan, Ann Arbor, USA. 2. Department of Neurology, the Third Xiangya Hospital, Central South University, Changsha, China. 3. Department of Pediatrics, University of Michigan, Ann Arbor, USA. 4. Department of Psychology, University of Michigan, Ann Arbor, USA. 5. Department of Psychiatry, University of Michigan, Ann Arbor, USA. 6. Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, USA.
Abstract
OBJECTIVES: Focal cortical dysplasia type II (FCDII) is one of the most common underlying pathologies in patients with drug-resistant epilepsy. However, mechanistic understanding of FCDII fails to keep pace with genetic discoveries, primarily due to the significant challenge in developing a clinically relevant animal model. Conceptually and clinically important questions, such as the unknown latent period of epileptogenesis and the controversial epileptogenic zone, remain unknown in all experimental FCDII animal models, making it even more challenging to investigate the underlying epileptogenic mechanisms. METHODS: In this study, we used continuous video-electroencephalography (EEG) monitoring to detect the earliest interictal and ictal events in a clustered regularly interspaced short palindromic repeats (CRISPR)-in utero electroporation (IUE) FCDII rat model that shares genetic, pathological, and electroclinical signatures with those observed in humans. We then took advantage of in vivo local field potential (LFP) recordings to localize the epileptogenic zone in these animals. RESULTS: To the best of our knowledge, we showed for the first time that epileptiform discharges emerged during the third postnatal week, and that the first seizure occurred as early as during the fourth postnatal week. We also showed that both interictal and ictal discharges are localized within the dysplastic cortex, concordant with human clinical data. SIGNIFICANCE: Together, our work identified the temporal and spatial frame of epileptogenesis in a highly clinically relevant FCDII animal model, paving the way for mechanistic studies at molecular, cellular, and circuitry levels.
OBJECTIVES:Focal cortical dysplasia type II (FCDII) is one of the most common underlying pathologies in patients with drug-resistant epilepsy. However, mechanistic understanding of FCDII fails to keep pace with genetic discoveries, primarily due to the significant challenge in developing a clinically relevant animal model. Conceptually and clinically important questions, such as the unknown latent period of epileptogenesis and the controversial epileptogenic zone, remain unknown in all experimental FCDII animal models, making it even more challenging to investigate the underlying epileptogenic mechanisms. METHODS: In this study, we used continuous video-electroencephalography (EEG) monitoring to detect the earliest interictal and ictal events in a clustered regularly interspaced short palindromic repeats (CRISPR)-in utero electroporation (IUE) FCDII rat model that shares genetic, pathological, and electroclinical signatures with those observed in humans. We then took advantage of in vivo local field potential (LFP) recordings to localize the epileptogenic zone in these animals. RESULTS: To the best of our knowledge, we showed for the first time that epileptiform discharges emerged during the third postnatal week, and that the first seizure occurred as early as during the fourth postnatal week. We also showed that both interictal and ictal discharges are localized within the dysplastic cortex, concordant with human clinical data. SIGNIFICANCE: Together, our work identified the temporal and spatial frame of epileptogenesis in a highly clinically relevant FCDII animal model, paving the way for mechanistic studies at molecular, cellular, and circuitry levels.
Authors: Sang Min Park; Jae Seok Lim; Suresh Ramakrishina; Se Hoon Kim; Woo Kyeong Kim; Junehawk Lee; Hoon-Chul Kang; Jeremy F Reiter; Dong Seok Kim; Hyongbum Henry Kim; Jeong Ho Lee Journal: Neuron Date: 2018-06-21 Impact factor: 17.173
Authors: Ingmar Blümcke; Maria Thom; Eleonora Aronica; Dawna D Armstrong; Harry V Vinters; Andre Palmini; Thomas S Jacques; Giuliano Avanzini; A James Barkovich; Giorgio Battaglia; Albert Becker; Carlos Cepeda; Fernando Cendes; Nadia Colombo; Peter Crino; J Helen Cross; Olivier Delalande; François Dubeau; John Duncan; Renzo Guerrini; Philippe Kahane; Gary Mathern; Imad Najm; Ciğdem Ozkara; Charles Raybaud; Alfonso Represa; Steven N Roper; Noriko Salamon; Andreas Schulze-Bonhage; Laura Tassi; Annamaria Vezzani; Roberto Spreafico Journal: Epilepsia Date: 2010-11-10 Impact factor: 5.864
Authors: Shuntong Hu; Robert C Knowlton; Brendon O Watson; Katarzyna M Glanowska; Geoffrey G Murphy; Jack M Parent; Yu Wang Journal: Ann Neurol Date: 2018-08-06 Impact factor: 10.422
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