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

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; ... (2021). A systems-level analysis highlights microglial activation as a modifying factor in common epilepsies. (In Press). Neuropathology and Applied Neurobiology Wiley 10.1111/nan.12758

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Radiology, Neuroradiology and Nuclear Medicine (DRNN) > Institute of Diagnostic and Interventional Neuroradiology

UniBE Contributor:

Rummel, Christian and Wiest, Roland

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1365-2990

Publisher:

Wiley

Language:

English

Submitter:

Martin Zbinden

Date Deposited:

01 Oct 2021 15:50

Last Modified:

01 Oct 2021 15:55

Publisher DOI:

10.1111/nan.12758

PubMed ID:

34388852

Uncontrolled Keywords:

MRI cortical thinning gene expression post mortem

BORIS DOI:

10.48350/159381

URI:

https://boris.unibe.ch/id/eprint/159381

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