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

2022-02

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

MRI

cortical thinning

gene expression

post mortem

Journal Article

0000-0002-9265-2393

0000-0001-7481-5198

0000-0002-3205-4631

0000-0003-4730-5322

0000-0001-7712-2629

10.1111/nan.12758

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

Neuropathology and applied neurobiology 2022; 48(1): e12758

Neuropathology and Applied Neurobiology