Altmann, AndreRyten, MinaNunzio, Martina DiRavizza, TeresaZhang, Guohaoet al2022-10-112022-10-112021-08-13Altmann, A, Ryten, M, Di Nunzio, M, et al. A systems-level analysis highlights microglial activation as a modifying factor in common epilepsies. Neuropathol Appl Neurobiol. 2022; 48( 1):e12758. doi:10.1111/nan.12758https://doi.org/10.1111/nan.12758http://hdl.handle.net/11603/26148Authors: Andre Altmann, Mina Ryten, Martina Di Nunzio, Teresa Ravizza, Daniele Tolomeo, Regina H. Reynolds, Alyma Somani, Marco Bacigaluppi, Valentina Iori, Edoardo Micotti, Rossella Di Sapia, Milica Cerovic, Eleonora Palma, Gabriele Ruffolo, Juan A. Botía, Julie Absil, Saud Alhusaini, Marina K. M. Alvim, Pia Auvinen, Nuria Bargallo, Emanuele Bartolini, Benjamin Bender, Felipe P. G. Bergo, Tauana Bernardes, Andrea Bernasconi, Neda Bernasconi, Boris C. Bernhardt, Karen Blackmon, Barbara Braga, Maria Eugenia Caligiuri, Anna Calvo, Chad Carlson, Sarah J. A. Carr, Gianpiero L. 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 K. Focke, Sonya Foley, Wendy Franca, Antonio Gambardella, Renzo Guerrini, Khalid Hamandi, Derrek P. Hibar, Dmitry Isaev, Graeme D. Jackson, Neda Jahanshad, Reetta Kälviäinen, Simon S. Keller, Peter Kochunov, Raviteja Kotikalapudi, Magdalena A. Kowalczyk, Ruben Kuzniecky, Patrick Kwan, Angelo Labate, Soenke Langner, Matteo Lenge, Min Liu, Pascal Martin, Mario Mascalchi, Stefano Meletti, Marcia E. Morita-Sherman, 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, Domenico 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 R. McDonald, Annamaria Vezzani, Sanjay M. SisodiyaAims The causes of distinct patterns of reduced cortical thickness in the common human epilepsies, detectable on neuroimaging and with important clinical consequences, are unknown. We investigated the underlying mechanisms of cortical thinning using a systems-level analysis. Methods Imaging-based cortical structural maps from a large-scale epilepsy neuroimaging study were overlaid with highly spatially resolved human brain gene expression data from the Allen Human Brain Atlas. Cell-type deconvolution, differential expression analysis and cell-type enrichment analyses were used to identify differences in cell-type distribution. These differences were followed up in post-mortem brain tissue from humans with epilepsy using Iba1 immunolabelling. Furthermore, to investigate a causal effect in cortical thinning, cell-type-specific depletion was used in a murine model of acquired epilepsy. Results We identified elevated fractions of microglia and endothelial cells in regions of reduced cortical thickness. Differentially expressed genes showed enrichment for microglial markers and, in particular, activated microglial states. Analysis of post-mortem brain tissue from humans with epilepsy confirmed excess activated microglia. In the murine model, transient depletion of activated microglia during the early phase of the disease development prevented cortical thinning and neuronal cell loss in the temporal cortex. Although the development of chronic seizures was unaffected, the epileptic mice with early depletion of activated microglia did not develop deficits in a non-spatial memory test seen in epileptic mice not depleted of microglia. Conclusions 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.15 pagesen-USThis item is likely protected under Title 17 of the U.S. Copyright Law. Unless on a Creative Commons license, for uses protected by Copyright Law, contact the copyright holder or the author.Attribution 3.0 United StatesText