Focal DEPDC5 loss without disruption to cerebral cortical neuron migration recapitulates DEPDC5-related focal epilepsy.

Abstract

Focal cortical dysplasia (FCD) is a major cause of refractory epilepsy and is associated with pathogenic variants in mTOR pathway genes, including DEPDC5, the most common cause of familial focal epilepsy. The mechanisms of epileptogenesis associated with FCD and hyperactive mTOR signaling remain unclear in DEPDC5-related epilepsy. To test whether DEPDC5 loss leading to seizures require in utero cortical developmental defects or if postnatal neuronal dysfunction of mTORC1 is sufficient to drive seizures, we developed a postnatal focal cortical Depdc5 knockout mouse model. Postnatal day 0-1 Depdc5-floxed mice received unilateral motor cortex injections of either AAV-Cre-GFP or control AAV-GFP. The AAV-Cre-GFP injected hemisphere had decreased DEPDC5 levels with hyperactivation of mTOR that increased with age compared to both the contralateral hemisphere and the AAV-GFP injected mice. Cortical lamination was not disrupted by postnatal DEPDC5 loss. Pathologic hallmarks of FCDs were identified in the Depdc5 knockout hemisphere, including increased SMI-311 neurofilament staining, hypomyelination, astrogliosis, and microglial activation. Mice with postnatal cortical DEPDC5 loss exhibited lower seizure thresholds, increased focal seizures, and increased rates of seizure-induced death compared to control mice. This study demonstrates that postnatal DEPDC5 loss and subsequent mTOR hyperactivation without disruption of cortical migration is sufficient to cause epilepsy.