Increased expression of chondroitin sulfate proteoglycans in dentate gyrus and amygdala causes postinfectious seizures

Abstract

Abstract Alterations in the extracellular matrix (ECM) are common in patients with epilepsy and in animal models of epilepsy, yet whether they are cause or consequence of seizures and epilepsy development is unknown. Using Theiler’s murine encephalomyelitis virus (TMEV) infection-induced model of acquired epilepsy, we find de novo expression of chondroitin sulfate proteoglycans (CSPGs), a major ECM component, in dentate gyrus (DG) and amygdala exclusively in mice with acute seizures. Preventing synthesis of CSPGs specifically in DG and amygdala by deletion of the major CSPG aggrecan reduced seizure burden. Patch-clamp recordings from dentate granule cells (DGCs) revealed enhanced intrinsic and synaptic excitability in seizing mice that was significantly ameliorated by aggrecan deletion. In situ experiments suggest that DGCs hyperexcitability results from negatively charged CSPGs increasing stationary cations on the membrane thereby depolarizing neurons, increasing their intrinsic and synaptic excitability. These results show increased expression of CSPGs in the DG and amygdala as one of the causal factors for TMEV-induced acute seizures. We also show identical changes in CSPGs in pilocarpine-induced epilepsy suggesting that enhanced CSPGs in the DG and amygdala may be a common ictogenic factor and potential therapeutic target.