Chondroitin sulfate proteoglycans (CSPGs) are predominant components of the extracellular matrix in the central nervous system (CNS). Previously, we found an increase in the 4-sulfation/6-sulfation (4S/6S) ratio of CSPGs is required for perineuronal net (PNN) formation and results in functional maturation of parvalbumin-expressing interneurons (PV cells) and termination of the critical period in the visual cortex. Here, we report that chondroitin 6-sulfation and chondroitin 6-sulfation-enriched PNNs increased in the mouse cerebral cortex and hippocampus after kainic acid (KA) treatment; simultaneously, chondroitin 4-sulfation-enriched PNNs and the 4S/6S ratio decreased. Furthermore, chondroitin 6-O-sulfotransferase-1 (C6ST-1) transgenic (TG) mice, which overexpress chondroitin 6-sulfated chains and have a decreased 4S/6S ratio, were more susceptible to KA-induced seizures than wild-type mice. These results suggested that chondroitin 6-sulfation is relevant to epilepsy most probably because of dysregulated PNN formation and PV cell maturation.