Toggle Main Menu Toggle Search

Open Access padlockePrints

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

Lookup NU author(s): Dr Rhys ThomasORCiD

Downloads


Licence

This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2021 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.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.


Publication metadata

Author(s): Altmann A, Ryten M, Di Nunzio M, Ravizza T, Tolomeo D, Reynolds RH, Somani A, Bacigaluppi M, Iori V, Micotti E, Di Sapia R, Cerovic M, Palma E, Ruffolo G, Botia JA, Absil J, Alhusaini S, Alvim MKM, Auvinen P, Bargallo N, Bartolini E, Bender B, Bergo FPG, Bernardes T, Bernasconi A, Bernasconi N, Bernhardt BC, Blackmon K, Braga B, Caligiuri ME, Calvo A, Carlson C, Carr SJA, Cavalleri GL, Cendes F, Chen J, Chen S, Cherubini A, Concha L, David P, Delanty N, Depondt C, Devinsky O, Doherty CP, Domin M, Focke NK, Foley S, Franca W, Gambardella A, Guerrini R, Hamandi K, Hibar DP, Isaev D, Jackson GD, Jahanshad N, Kalviainen R, Keller SS, Kochunov P, Kotikalapudi R, Kowalczyk MA, Kuzniecky R, Kwan P, Labate A, Langner S, Lenge M, Liu M, Martin P, Mascalchi M, Meletti S, Morita-Sherman ME, O'Brien TJ, Pariente JC, Richardson MP, Rodriguez-Cruces R, Rummel C, Saavalainen T, Semmelroch MK, Severino M, Striano P, Thesen T, Thomas RH, Tondelli M, Tortora D, Vaudano AE, Vivash L, von Podewils F, Wagner J, Weber B, Wiest R, Yasuda CL, Zhang G, Zhang J, Leu C, Avbersek A, Thom M, Whelan CD, Thompson P, McDonald CR, Vezzani A, Sisodiya SM

Publication type: Article

Publication status: Published

Journal: Neuropathology and Applied Neurobiology

Year: 2021

Pages: epub ahead of print

Online publication date: 13/08/2021

Acceptance date: 15/07/2021

Date deposited: 22/09/2021

ISSN (print): 0305-1846

ISSN (electronic): 1365-2990

Publisher: John Wiley and Sons Inc

URL: https://doi.org/10.1111/nan.12758

DOI: 10.1111/nan.12758

PubMed id: 34388852


Altmetrics

Altmetrics provided by Altmetric


Funding

Funder referenceFunder name
European Union (7th Framework Programme [FP7 Ideas: European Research Council] Grants 279062, EpiPGX and 602102, EPITARGET)
Medical Research Council (grant number MR/L016311/1).
National Institutes of Health (NIH) Grants R01 NS097719 (M.E.M.), U54 EB020403 (P.T.) and NIH/NINDS R01 NS065838 (C.R.M.).

Share