1. A systems-level analysis highlights microglial activation as a modifying factor in common epilepsies
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Daniele Tolomeo, Chantal Depondt, Teresa Ravizza, Reetta Kälviäinen, Jose C. Pariente, Renzo Guerrini, Jan Wagner, Guohao Zhang, Paul M. Thompson, Niels K. Focke, Pia Auvinen, Christopher D. Whelan, Derrek P. Hibar, Philippe David, Magdalena A. Kowalczyk, Neda Bernasconi, Matteo Lenge, Martin Domin, Rhys H. Thomas, Edoardo Micotti, Shuai Chen, Peter Kochunov, Felix von Podewils, Domenico Tortora, Antonio Gambardella, Manuela Tondelli, Andrea Cherubini, Costin Leu, Simon S. Keller, Wendy Franca, Stefano Meletti, Andrea Bernasconi, Pasquale Striano, Rossella Di Sapia, Andreja Avbersek, Thomas Thesen, Khalid Hamandi, Luis Concha, Mario Mascalchi, Clarissa L. Yasuda, Neda Jahanshad, Patrick Kwan, Min Liu, Marcia Morita-Sherman, Alyma Somani, Mina Ryten, Dmitry Isaev, Gabriele Ruffolo, Ruben Kuzniecky, Chad Carlson, Anna Calvo, Angelo Labate, Colin P. Doherty, Mark P. Richardson, Milica Cerovic, Raviteja Kotikalapudi, Sonya Foley, Felipe P. G. Bergo, Barbara Braga, Julie Absil, Graeme D. Jackson, Sarah J. A. Carr, Boris C. Bernhardt, Núria Bargalló, Roland Wiest, Mira Semmelroch, Carrie R. McDonald, Martina Di Nunzio, Anna Elisabetta Vaudano, Raúl Rodríguez-Cruces, Mariasavina Severino, Marina K. M. Alvim, Taavi Saavalainen, Gianpiero L. Cavalleri, Eleonora Palma, Regina H. Reynolds, Pascal Martin, Christian Rummel, Andre Altmann, Tauana Bernardes, Fernando Cendes, Annamaria Vezzani, Soenke Langner, Norman Delanty, Sanjay M. Sisodiya, Karen Blackmon, Valentina Iori, Terence J. O'Brien, Orrin Devinsky, Maria Eugenia Caligiuri, Jian Chen, Bernd Weber, Junsong Zhang, Emanuele Bartolini, Marco Bacigaluppi, Benjamin Bender, Maria Thom, Lucy Vivash, Juan A. Botía, and Saud Alhusaini
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Histology ,cortical thinning ,610 Medicine & health ,Biology ,Article ,Pathology and Forensic Medicine ,03 medical and health sciences ,Epilepsy ,GABA ,Mice ,0302 clinical medicine ,Neuroimaging ,Seizures ,Physiology (medical) ,Gene expression ,medicine ,Animals ,Neuroinflammation ,030304 developmental biology ,post mortem ,Temporal cortex ,0303 health sciences ,Microglia ,epilepsy ,gene expression ,Brain ,Endothelial Cells ,Human brain ,Acquired immune system ,medicine.disease ,medicine.anatomical_structure ,Neurology ,MRI ,Neurology (clinical) ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Aims\ud 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.\ud \ud Methods\ud 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.\ud \ud Results\ud 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.\ud \ud Conclusions\ud 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.
- Published
- 2021
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