HMGB1-RAGE Pathway Contributes to the Abnormal Migration of Endogenous Subventricular Zone Neural Progenitors in an Experimental Model of Focal Microgyria

Abstract

Abnormal migration of subventricular zone (SVZ)-derived neural progenitor cells (SDNPs) is involved in the pathological and epileptic processes of focal cortical dysplasia (FCD), but the underlying mechanisms are still unclear. Recent studies have indicated that high mobility group box 1 (HMGB1)/receptor for advanced glycation end products (RAGE) is widely expressed in epileptic specimens of FCD, suggesting that the HMGB1-RAGE pathway may be involved in the pathological and/or epileptic processes of FCD. In the present study, by using Nestin-GFP tg/+ transgenic mice, we established a model of freezing lesion (FL), as described in our previous report. A "migrating stream", which was composed of GFP-Nestin + SDNPs, was derived from the SVZ region and migrated to the cortical FL area. We found that translocated HMGB1 and RAGE were expressed in cortical lesion in a clustered distribution pattern, which was especially obvious in the early stage of FL compared with the sham group. Interestingly, the number of GFP-Nestin + SDNPs within the migrating stream was signi cantly decreased when the HMGB1-RAGE pathway was blocked by an antagonist of RAGE or deletion of the RAGE gene. Moreover, the absence of RAGE also decreased the activity of pentylenetetrazol-induced cortical epileptiform discharge. In summary, this study provided experimental evidence that in the early stage of FL, the levels of extranuclear HMGB1 and its receptor RAGE were increased in cortical lesion in the FL model. Activation of the HMGB1-RAGE pathway may contribute to the abnormal migration of SDNPs and the hyperexcitability of cortical lesion in the FL model.