mTOR-driven neural circuit changes initiate an epileptogenic cascade

•Low levels of Pten KO hippocampal granule cells produce subclinical brain hyperexcitability.•High Pten KO granule cell loads are associated with generalized seizures and interneuron loss.•Pten KO granule cells mediate the formation of recurrent excitatory circuits.•Pten KO cells initiate secondary changes in surrounding, initially normal neuronal circuits. Mutations in genes regulating mTOR pathway signaling are now recognized as a significant cause of epilepsy. Interestingly, these mTORopathies are often caused by somatic mutations, affecting variable numbers of neurons. To better understand how this variability affects disease phenotype, we developed a mouse model in which the mTOR pathway inhibitor Pten can be deleted from 0 to 40 % of hippocampal granule cells. In vivo, low numbers of knockout cells caused focal seizures, while higher numbers led to generalized seizures. Generalized seizures coincided with the loss of local circuit interneurons. In hippocampal slices, low knockout cell loads produced abrupt reductions in population spike threshold, while spontaneous excitatory postsynaptic currents and circuit level recurrent activity increased gradually with rising knockout cell load. Findings demonstrate that knockout cells load is a critical variable regulating disease phenotype, progressing from subclinical circuit abnormalities to electrobehavioral seizures with secondary involvement of downstream neuronal populations.