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A systems-level analysis highlights microglial activation as a modifying factor in common forms of human epilepsy

By Andre Altmann, Mina Ryten, Martina Di Nunzio, Teresa Ravizza, Daniele Tolomeo, Regina H Reynolds, Alyma Somani, Marco Bacigaluppi, Valentina Iori, Edoardo Micotti, Juan A Botia, Julie Absil, Saud Alhusaini, Marina K. M. Alvim, Pia Auvinen, Nuria Bargallo, Emanuele Bartolini, Benjamin Bender, Felipe Bergo, Tauana Bernardes, Andrea Bernasconi, Neda Bernasconi, Boris C Bernhardt, Karen Blackmon, Barbara Braga, Maria E Caligiuri, Anna Cavalo, Chad Carlson, Sarah Carr, Gianpiero Cavalleri, Fernando Cendes, Jian Chen, Shuai Chen, Andrea Cherubini, Luis Concha, Philippe David, Norman Delanty, Chantal Depondt, Orrin Devinsky, Colin P. Doherty, Martin Domin, Niels Focke, Sonya Foley, Wendy Franca, Antonio Gambardella, Renzo Guerrini, Khalid Hamandi, Derrek P Hibar, Dmitry Y Isaev, Graeme Jackson, Neda Jahanshad, Reetta Kalviainen, Simon Keller, Peter Kochunov, Raviteja Kotikalapudi, Magdalena A Kowalczyk, Ruben Kuzniecky, Patrick Kwan, Angelo Labate, Soenke Langer, Matteo Lenge, Min Liu, Pascal Martin, Mario Mascalchi, Stefano Meletti, Marcia E Morita, Terence J O'Brien, Jose C Pariente, Mark P Richardson, Raul Rodriguez-Cruces, Christian Rummel, Taavi Saavalainen, Mira K Semmelroch, Mariasavina Severino, Pasquale Striano, Thomas Thesen, Rhys H Thomas, Manuela Tondelli, Domenica Tortora, Anna Elisabetta Vaudano, Lucy Vivash, Felix von Podewils, Jan Wagner, Bernd Weber, Roland Wiest, Clarissa L. Yasuda, Guohao Zhang, Junsong Zhang, ENIGMA-Epilepsy Working Group, Costin Leu, Andreja Avbersek, EpiPGX Consortium, Maria Thom, Christopher D. Whelan, Paul Thompson, Carrie McDonald, Annamaria Vezzani, Sanjay M. Sisodiya

Posted 14 Nov 2018
bioRxiv DOI: 10.1101/470518

The 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.

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