Abstract
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.
Highlights
Significant progress is being made in understanding disease processes in the epilepsies
labelling index (LI) was measured across 14 regions of interest (ROIs) in post-mortem brain tissue derived from 55 individuals, comprising individuals with non-lesional epilepsy (EP-NL, n = 18), lesional epilepsy (EP-L, n = 21) and non-epilepsy controls (NEC, n = 16)
We investigated enrichment of differentially expressed genes in Gene Ontology (GO) terms and Kyoto Encyclopaedia of Genes and Genomes (KEGG) and REACTOME pathways using a threshold-free approach based on the area under the receiver operator characteristics curve (AUC) [24]
Summary
Significant progress is being made in understanding disease processes in the epilepsies. Known causes per se may not explain all the observed outcomes, suggesting that many epilepsies could be conceptualised as intricate matrices of causation, processes and outcomes [7], with complex inter-dependencies, such as a likely link between reduction in cortical thickness and disease duration [8]. Allen Institute [15, 16] to direct interrogation of regionalised brain cell-type composition and generic biological processes that might underlie thickness or volume reductions across the studied epilepsy syndromes. We hypothesised that this approach could suggest disease mechanisms causing the observed structural changes. Our new results implicate microglia in the widespread, but largely unstudied, reduction in cortical thickness that accompanies the numerically far more important common human epilepsies and point to the potential for prevention of such thinning by manipulation of microglia
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