Schinzel-Giedion syndrome (SGS), a rare developmental disorder characterized by congenital anomalies, intellectual impairment and epilepsy, is attributed to de novo point mutations affecting SET binding protein 1 (SETBP1). These mutations lead to pathological protein accumulation, triggering a cascade of downstream effects, partially understood. Considering the significant neurological consequences of such germline mutations, it is reasonable to speculate that SETBP1 plays a crucial role during central nervous system development, although limited data are available. To dissect SGS epileptogenesis, a mouse model harboring the mutated SETBP1 gene was crossbred with various Cre driver lines to spatio-temporally modulate the pathological protein accumulation. Consistently with patients, mutant mice with widespread SETBP1 accumulation in the brain display seizure predisposition, arising from hyperactive dentate gyrus’ granule cells. Interestingly, restricting the accumulation to the excitatory compartment (excitatory-specific mutants) prevents epileptic symptoms, despite granule cells retaining their hyperexcitability. This data suggests that the principal neuron impairment alone is not sufficient for seizure initiation. However, interneuron-specific mutants show no seizure vulnerability, implying that an inhibitory neuron impairment, in addition to the excitatory one, is necessary for the epileptic phenotype to arise. Therefore in our models, both neuronal populations cooperate to establish a novel, either unsuccessful or successful, excitation/inhibition balance determining seizure vulnerability. In conclusion, these findings offer insight into the complex interplay between excitatory and inhibitory elements within the neural circuitry, impacted by SETBP1 accumulation. Specifically, this spatiotemporal approach elucidates the necessity for both neuronal compartments to be concomitantly affected, proposing a pathological double-hit mechanism underlying SGS epileptic phenotype.