Somatic mutations in mechanistic target of rapamycin (mTOR) pathway genes produce focal brain malformations that can lead to epilepsy. Malformations show a high degree of mosaicism, sometimes with less than 1% of neurons carrying the mutation. Seizures are hypothesized to be driven by mutation-carrying dysmorphic excitatory neurons, but lesions in patients and animal models also show loss of interneurons. Here, we queried whether interneuron loss could act as a second hit, releasing the brake on excitatory dysmorphic neurons and increasing epilepsy severity. To test this hypothesis, we developed a two-hit mouse model in which we combined loss of the mTOR pathway inhibitor phosphatase and tensin homologue (Pten) from excitatory hippocampal dentate granule cells with ablation of local parvalbumin or somatostatin interneurons. Pten was deleted from roughly 3% of granule cells, a level which is subthreshold for producing frequent generalized seizures, thus facilitating assessment for synergistic effects. Pten loss alone produced occasional seizures, while interneuron ablation alone initiated frequent seizures lasting for about one week, followed by a significant decline in seizure incidence in subsequent weeks. The combination of Pten deletion and interneuron ablation did not produce a synergistic increase in seizure incidence over ablation alone. Findings confirm the potential for interneuron loss to drive epileptogenesis, but do not support the hypothesis that rapid disinhibition of Pten knockout granule cells enhances their ictogenic potential. Results provide new insights into the role of GABAergic inhibitory input in regulating the activity of mTOR hyperactive neurons. • Pten KO granule cells are densely coated with inhibitory synaptic terminals • Ablation of parvalbumin or somatostatin interneurons leads to epilepsy in mice • Pten KO plus interneuron loss does not synergistically increase epilepsy severity • Data does not support a two-hit mechanism of epileptogenesis in an mTORopathy model
Drake et al. (Fri,) studied this question.