Barry, J. M. | bioRxiv Science

bioRxiv2026

Scaling of Neuronal Growth and Excitability Through Separable mTORC1 and mTORC2 Pathways

As neurons grow, they must regulate intrinsic excitability to maintain an appropriate level of spiking based on synaptic inputs. Using gene knockouts, phosphoproteomics, and electrophysiology we show PTEN regulates neuronal growth and intrinsic excitability through separable downstream mechanisms. Pten loss induces cellular hypertrophy, increased excitatory synaptic input, reduced fast afterhyperpolarization, and burst firing. Deleting the mTORC1 scaffold, Raptor, rescues overgrowth and synaptic input but fails to normalize firing, while deleting Akt or the mTORC2 scaffold, Rictor, restores firing without rescuing growth. This dissociation identifies an AKT-mTORC2 mechanism that regulates voltage-gated calcium and BK potassium channels to set spike repolarization and burst firing. In vivo, Pten knockout produces altered network synchrony, lethal seizures, and impaired object and location behavior; Raptor co-deletion display non-lethal hyperexcitability with improved object-location coupling. The biological and pathophysiological significance of these mechanisms is demonstrated by overlap of the PTEN-regulated phosphoproteome with ASD and epilepsy.

neuroscience↗

bioRxiv2018

State conditional optogenetic entrainment of the septo-hippocampal circuit reveals the importance of endogenous theta oscillations as a unit of spatial metric

The manipulation of pattern generators in order to impose temporal organization on target nodes while accounting for dynamic changes in behavior and cognitive demand remains a significant challenge for the use of neurostimulation as a therapeutic treatment option. While perturbation through optogentic stimulation can reveal circuit mechanisms that create and locally integrate temporal organization, it is unclear whether superseding endogenous signals with artificial oscillations would benefit or impede hippocampus-dependent cognition or how cognitive demand might affect artificial septo-hippocampal entrainment. Optogenetic MS stimulation in wild-type rats in 3 conditions showed that septal input is more likely to supersede endogenous hippocampal LFP oscillations when animals are at rest or performing a hippocampus-dependent spatial accuracy task. Stimulation during a hippocampus-independent task, however, resulted in compensatory endogenous oscillations. Although stimulation effects on the inter-spike interval of hippocampal pyramidal cells mirrored task-conditional theta entrainment of the LFP, place field properties were unaffected. Analyses of spatial behavior indicate that optogenetic stimulation can attenuate performance and specific measures of goal zone estimation accuracy but otherwise does not affect the rats ability to navigate to the target quadrant. The results suggest that the behavioral effect of temporally organizing the septo-hippocampal circuit relative to an artificial theta signal is limited to the accuracy of the rats approximation of the goal zone location. These results have significant implications for the therapeutic use of optogenetic stimulation as a means of attenuating cognitive deficits associated with temporal discoordination.

neuroscience↗