A systems-level analysis highlights microglial activation as a modifying factor in common epilepsies

Journal article


Altmann, Andre, Ryten, Mina, Di Nunzio, Martina, Ravizza, Teresa, Tolomeo, Daniele, Reynolds, Regina H., Somani, Alyma, Bacigaluppi, Marco, Iori, Valentina, Micotti, Edoardo, Di Sapia, Rossella, Cerovic, Milica, Palma, Eleonora, Ruffolo, Gabriele, Botía, Juan A., Absil, Julie, Alhusaini, Saud, Alvim, Marina K. M., Auvinen, Pia, ... Sisodiya, Sanjay M.. (2022). A systems-level analysis highlights microglial activation as a modifying factor in common epilepsies. Neuropathology and Applied Neurobiology. 48(1), p. Article e12758. https://doi.org/10.1111/nan.12758
AuthorsAltmann, Andre, Ryten, Mina, Di Nunzio, Martina, Ravizza, Teresa, Tolomeo, Daniele, Reynolds, Regina H., Somani, Alyma, Bacigaluppi, Marco, Iori, Valentina, Micotti, Edoardo, Di Sapia, Rossella, Cerovic, Milica, Palma, Eleonora, Ruffolo, Gabriele, 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. A., 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, Kälviäinen, Reetta, Keller, Simon S., Kochunov, Peter, Kotikalapudi, Raviteja, Kowalczyk, Magdalena, Kuzniecky, Ruben, Kwan, Patrick, Labate, Angelo, Langner, Soenke, Lenge, Matteo, Liu, Min, Martin, Pascal, Mascalchi, Mario, Meletti, Stefano, Morita-Sherman, 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, ENIGMA-Epilepsy Working Group, Leu, Costin, Avbersek, Andreja, EpiPGX Consortium, Thom, Maria, Whelan, Christopher D., Thompson, Paul, McDonald, Carrie R., Vezzani, Annamaria and Sisodiya, Sanjay M.
Abstract

Aims
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.

Keywordscortical thinning; gene expression; MRI; post mortem
Year2022
JournalNeuropathology and Applied Neurobiology
Journal citation48 (1), p. Article e12758
PublisherJohn Wiley & Sons Ltd
ISSN0305-1846
Digital Object Identifier (DOI)https://doi.org/10.1111/nan.12758
PubMed ID34388852
Scopus EID2-s2.0-85114315833
PubMed Central IDPMC8983060
Open accessPublished as ‘gold’ (paid) open access
Page range1-15
Publisher's version
License
File Access Level
Open
Output statusPublished
Publication dates
Online05 Sep 2021
Publication process dates
Accepted15 Jul 2021
Deposited16 Dec 2021
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