OBJECTIVE: Loss-of-function mutations in the GIRDIN/CCDC88A gene cause developmental epileptic encephalopathy (DEE) in humans. However, its pathogenesis is largely unknown. Global knockout mice of the corresponding orthologous gene (gKOs) have a preweaning lethal phenotype with growth failure, preventing longitudinal analysis. We aimed to overcome this lethality and elucidate DEE pathogenesis. METHODS: We developed a novel lifelong feeding regimen (NLFR), which consists of providing mash food from postnatal day 14 (P14) until weaning (P28), followed by agar-bound food exclusively after weaning. Videography, electroencephalography (EEG), and histological analyses were performed. Conditional Girdin/Ccdc88a knockout mice (cKOs) of variable lineages (Nestin, Emx1, or Nkx2-1) were generated to identify the region responsible for epilepsy. RESULTS: Under the NLFR, gKOs survived beyond 1 year and displayed fully penetrant, robust epileptic phenotypes, including early-onset (P22.3 in average) generalized tonic-clonic seizures (GTCSs) (averaging eight per day), which were completely synchronized with fast rhythms on EEG, frequent interictal electroencephalographic spikes (averaging 430 per hour), and progressive deformation of visceral organs. In addition, gKOs had absence seizures, which were not always time-locked to frequent spike waves on EEG. The frequent GTCSs and interictal spikes in gKOs were suppressed by known antiepileptic drugs. Histologically, bilateral hippocampi in gKOs exhibited congenital cornu-ammonis splitting, granule cell dispersion, and astrogliosis. Furthermore, analysis of conditional knockouts using multiple Cre-deleters identified a defect in the delivery of interneuron precursors from the medial ganglionic eminence into the hippocampal primordium during embryogenesis as a major cause of epileptogenesis. SIGNIFICANCE: These findings give rise to a new approach of lifelong caregiving to overcome the problem of preweaning lethality in animal models. We propose a useful model for studying DEE with hippocampal sclerosis and interneuronopathy. gKOs with NLFR combine the contradictory properties of robust epileptic phenotypes and long-term survivability, which can be used to investigate spontaneous epileptic wave propagation and therapeutic intervention in hippocampal sclerosis.