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Title
A systems-level analysis highlights microglial activation as a modifying factor in common epilepsies.
Publication Date
2022-02
Author(s)
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
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-Sherman, Marcia E
O'Brien, Terence J
Pariente, Jose C
Richardson, Mark P
Rodriguez-Cruces, Raul
Rummel, Christian
Saavalainen, Taavi
Semmelroch, Mira K H G
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
Thom, Maria
Whelan, Christopher D
Thompson, Paul
McDonald, Carrie R
Vezzani, Annamaria
Sisodiya, Sanjay M
Subject
MRI
cortical thinning
gene expression
post mortem
Type of document
Journal Article
OrcId
0000-0002-9265-2393
0000-0001-7481-5198
0000-0002-3205-4631
0000-0003-4730-5322
0000-0001-7712-2629
DOI
10.1111/nan.12758
Abstract
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. 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. 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. 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.
Link
Citation
Neuropathology and applied neurobiology 2022; 48(1): e12758
Jornal Title
Neuropathology and Applied Neurobiology

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