Although there are many disorders associated with impaired plasticity, this paper will highlight the clinical features, neurobiology associated with dysregulation of mTOR, preclinical studies, and clinical trials in tuberous sclerosis complex (TSC), neurofibromatosis-1 (NF1), and fragile X syndrome (FXS), as well as phosphatase and tensin homolog hamartoma syndromes (PTHS), neurogenetic disorders linked by abnormalities in synaptic plasticity and mTOR (mammalian target of rapamycin) signaling. Here, MTOR is linked to Pitt-Hopkins syndrome.