Mechanistic target of rapamycin (mTOR) signaling is mediated through mTORC1 and mTORC2. mTORC1 signaling requires the regulatory protein Raptor, while mTORC2 signaling requires Rictor. mTOR signaling is increased during epileptogenesis, and manipulations to inhibit mTOR have been shown to reduce seizure incidence in some epilepsy models. Inhibiting mTOR signaling is hypothesized to prevent epileptogenic changes. To test this hypothesis, and to assess how mTORC1 and mTORC2 might modulate epileptogenesis, we deleted Raptor or Rictor from a subset of hippocampal dentate granule cells in male and female mice to cell-autonomously inhibit mTORC1 or mTORC2, respectively. Gene deletion effects were examined in healthy mice and following status epilepticus, which leads to the development of epilepsy. Raptor and Rictor knockout cells had fewer dendritic spines than neighboring wildtype cells, and Raptor knockout cells had reduced presynaptic terminal volume and contributed less to mossy fiber axon sprouting. Raptor deletion decreased somatic contact with parvalbumin inhibitory neuron puncta and reduced soma area, while Rictor knockout cells were more likely to be c-Fos immunoreactive. Findings demonstrate that Raptor and Rictor deletion exert mixed effects on morphological changes associated with epilepsy, implying that mTORC1 and mTORC2 have both overlapping and distinct neuroanatomical targets. In addition, the magnitude of gene deletion effects was similar in saline and SE-exposed animals. The observation implies that rather than specifically blocking epileptogenic circuit rewiring in acquired epilepsy, mTOR inhibition acts similarly on granule cells in healthy and epileptic mice to produce mixed changes on structures underlying excitatory and inhibitory synaptic transmission.The mTOR signaling pathway is a critical regulator of cell growth and metabolism, and is implicated in the development of numerous diseases, including cancer, autism and epilepsy. mTOR signaling is mediated through two arms, mTORC1 and mTORC2. Here, we manipulated signaling through the two arms to assess the impact on neuronal structure in control and epileptic brains. Manipulating mTORC1 and mTORC2 signaling produced both overlapping and distinct effects on neuronal structure - in some cases offsetting changes associated with epilepsy, but in most cases producing similar effects in healthy and epileptic animals. Findings provide new insights into the role of mTOR signaling in epilepsy, and guidance for predicting off target effects of mTOR antagonism. Significance Statement
