Figure 6

Increased expression of astrocytic pSmad2 and reduced association of PNNs around PV(+) cells in human epileptic hippocampi. (a) Representative micrographs of human hippocampi stained for GFAP and phosphorylated Smad2, a downstream effecter of TGFβ signaling. The hippocampi were resected from temporal lobe epilepsy (TLE) patients or age-matched autopsy controls. Representative GFAP(+) astrocytes expressing pSmad2(+) are indicated by white arrowheads. Scale bar = 50 μm. (b) Co-localization of pSmad2 with GFAP was increased in TLE patients (n = 5) compared to controls (n = 3). (c) Representative confocal micrographs of human hippocampal tissues stained for GFAP, PV, and PNNs (WFA) resected from TLE patients or controls. Scale bar = 50 μm. White and blue arrowheads indicate representative PV(+)/WFA(+) and PV(+)/WFA(−) cells, respectively. (d) The percentage of PV(+)/WFA(+) cells was decreased in the hippocampus of TLE patients (n = 4) compared to controls (n = 4). Mann-Whitney test, two-tailed, was used for statistical analyses. *p < 0.05. (e) A working model. Several points for feed-forward loops (i-iii) can lead to chronic hyperexcitability and the development of epilepsy. The dysfunction of blood-brain barrier (BBB) and the ensuing entry of albumin into brain parenchyma activate TGFβ signaling. Comparative transcriptome analyses predicted the activation of the common core signaling transduction including MAPK pathway, Stat3, NFκB, AP-1, and ETS1. These signaling pathways can elicit the reciprocal activation of inflammation and extracellular matrix (ECM) remodeling (i). ECM remodeling can trigger the transformation of a latent from of TGFβ to its active form⁷⁵ as well as exacerbate BBB dysfunction⁵⁸ (ii). The degradation of perineuronal nets (PNNs) around fast-spiking interneurons and aberrant excitatory synaptogenesis occur in the course of ECM remodeling, presumably leading to functional alterations in inhibition and abnormality in synaptic plasticity that may contribute to excitation/inhibition (E/I) imbalance and ultimately the occurrence of seizures. Finally, seizures per se cause BBB dysfunction, inflammation, and the upregulation of MMPs activity^{31, 43} (iii).