A systems-level analysis highlights microglial activation as a modifying factor in common forms of human epilepsy
Author:
Altmann AndreORCID, Ryten Mina, Di Nunzio Martina, Ravizza Teresa, Tolomeo Daniele, Reynolds Regina H, Somani Alyma, Bacigaluppi Marco, Iori Valentina, Micotti Edoardo, Botía Juan A., Absil Julie, Alhusaini Saud, Alvim Marina K. M., Auvinen Pia, Bargallo Nuria, Bartolini Emanuele, Bender Benjamin, Bergo Felipe P. G., Bernardes Tauana, Bernasconi Andrea, Bernasconi Neda, Bernhardt Boris C., Blackmon Karen, Braga Barbara, Caligiuri Maria Eugenia, Calvo Anna, Carlson Chad, Carr Sarah J., Cavalleri Gianpiero L., Cendes Fernando, Chen Jian, Chen Shuai, Cherubini Andrea, Concha Luis, David Philippe, Delanty Norman, Depondt Chantal, Devinsky Orrin, Doherty Colin P., Domin Martin, Focke Niels K., Foley Sonya, Franca Wendy, Gambardella Antonio, Guerrini Renzo, Hamandi Khalid, Hibar Derrek P., Isaev Dmitry, Jackson Graeme D., Jahanshad Neda, Kalviainen Reetta, Keller Simon S., Kochunov Peter, Kotikalapudi Raviteja, Kowalczyk Magdalena A., Kuzniecky Ruben, Kwan Patrick, Labate Angelo, Langner Soenke, Lenge Matteo, Liu Min, Martin Pascal, Mascalchi Mario, Meletti Stefano, Morita Marcia E., O’Brien Terence J., Pariente Jose C., Richardson Mark P., Rodriguez-Cruces Raul, Rummel Christian, Saavalainen Taavi, Semmelroch Mira K., Severino Mariasavina, Striano Pasquale, Thesen Thomas, Thomas Rhys H., Tondelli Manuela, Tortora Domenico, Vaudano Anna Elisabetta, Vivash Lucy, von Podewils Felix, Wagner Jan, Weber Bernd, Wiest Roland, Yasuda Clarissa L., Zhang Guohao, Zhang Junsong, Leu Costin, Avbersek Andreja, Thorn Maria, Whelan Christopher D, Thompson Paul, McDonald Carrie, Vezzani Annamaria, Sisodiya Sanjay M, ,
Abstract
AbstractThe common human epilepsies are associated with distinct patterns of reduced cortical thickness, detectable on neuroimaging, with important clinical consequences. To explore underlying mechanisms, we layered MRI-based cortical structural maps from a large-scale epilepsy neuroimaging study onto highly spatially-resolved human brain gene expression data, identifying >2,500 genes overexpressed in regions of reduced cortical thickness, compared to relatively-protected regions. The resulting set of differentially-expressed genes shows enrichment for microglial markers, and in particular, activated microglial states. Parallel analyses of cell-specific eQTLs show enrichment in human genetic signatures of epilepsy severity, but not epilepsy causation. Post mortem brain tissue from humans with epilepsy shows excess activated microglia. In an experimental model, depletion of activated microglia prevents cortical thinning, but not the development of chronic seizures. These convergent data strongly implicate activated microglia in cortical thinning, representing a new dimension for concern and disease modification in the epilepsies, potentially distinct from seizure control.
Publisher
Cold Spring Harbor Laboratory
Cited by
8 articles.
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