A systems-level analysis highlights microglial activation as a modifying factor in common forms of human epilepsy



Altmann, Andre ORCID: 0000-0002-9265-2393, Ryten, Mina, Di Nunzio, Martina, Ravizza, Teresa ORCID: 0000-0002-9578-018X, Tolomeo, Daniele, Reynolds, Regina, Somani, Alyma, Bacigaluppi, Marco, Iori, Valentina, Micotti, Edoardo
et al (show 88 more authors) (2018) A systems-level analysis highlights microglial activation as a modifying factor in common forms of human epilepsy.

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Abstract

Abstract The common human epilepsies are associated with distinct patterns of reduced cortical thickness, detectable on neuroimaging, with important clinical consequences. To explore underlying mechanisms, we layered MRI-based cortical structural maps from a large-scale epilepsy neuroimaging study onto highly spatially-resolved human brain gene expression data, identifying >2,500 genes overexpressed in regions of reduced cortical thickness, compared to relatively-protected regions. The resulting set of differentially-expressed genes shows enrichment for microglial markers, and in particular, activated microglial states. Parallel analyses of cell-specific eQTLs show enrichment in human genetic signatures of epilepsy severity, but not epilepsy causation. Post mortem brain tissue from humans with epilepsy shows excess activated microglia. In an experimental model, depletion of activated microglia prevents cortical thinning, but not the development of chronic seizures. 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.

Item Type: Article
Uncontrolled Keywords: ENIGMA-Epilepsy Working Group, EpiPGX Consortium
Depositing User: Symplectic Admin
Date Deposited: 18 Dec 2019 16:32
Last Modified: 29 Sep 2020 08:13
DOI: 10.1101/470518
URI: http://livrepository.liverpool.ac.uk/id/eprint/3066960