A systems‐level analysis highlights microglial activation as a modifying factor in common epilepsies
Authors: 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. 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 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. , 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 , Sisodiya Sanjay M. 
Published: August 2021

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.