The mTOR pathway genesmTOR,Rheb,Depdc5,Pten, andTsc1have convergent and divergent impacts on cortical neuron development and function

Abstract

ABSTRACTBrain somatic mutations in various components of the mTOR complex 1 (mTORC1) pathway have emerged as major causes of focal malformations of cortical development and intractable epilepsy. While these distinct gene mutations converge on excessive mTORC1 signaling and lead to common clinical manifestations, it remains unclear whether they cause similar cellular and synaptic disruptions underlying cortical network hyperexcitability. Here, we show thatin uteroactivation of the mTORC1 activators,RhebormTOR, or biallelic inactivation of the mTORC1 repressors,Depdc5,Tsc1, orPtenin mouse medial prefrontal cortex leads to shared alterations in pyramidal neuron morphology, positioning, and membrane excitability but different changes in excitatory synaptic transmission. Our findings suggest that, despite converging on mTORC1 signaling, mutations in different mTORC1 pathway genes differentially impact cortical excitatory synaptic activity, which may confer gene-specific mechanisms of hyperexcitability and responses to therapeutic intervention.