DEPDC5, the key gene within the mechanistic target of rapamycin (mTOR) pathway, is one of the most common causative genes in patients with epilepsy and malformation of cortical development (MCD). Although somatic mutations in the dorsal cortical progenitors generate the malformed cortex, its pathogenesis of hyperexcitability is complex and remains unclear. We specifically deleted Depdc5 in the mouse forebrain dorsal progenitors to model DEPDC5-related epilepsy and investigated whether and how parvalbumin interneurons were non-cell autonomously affected in the malformed cortex. We showed that long before seizures, coincident with microglia inflammation, proteolytic enzymes degraded perineuronal nets (PNNs) in the malformed cortex, resulting in parvalbumin (PV+) interneuron loss and presynaptic inhibition impairment. Our studies, therefore, uncovered the hitherto unknown role of PNN in mTOR-related MCD, providing a new framework for mechanistic-based therapeutic development.