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Lookup NU author(s): Dr Rhys ThomasORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 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.
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: 2022
Volume: 48
Issue: 1
Print publication date: 17/01/2022
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
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