The Role of GATOR1 in Cortical Malformations

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PROJECT SUMMARY Malformations of cortical development (MCD) are a group of neurodevelopmental disorders characterized by a range of morphological and structural abnormalities of the cerebral cortex reflecting errors in embryonic brain development. MCD are associated with medically refractory epilepsy and may require the surgical removal of the affected brain tissue. Some MCD result from somatic mutations occurring in neuroglial progenitor cells that result in abnormal cortical development in a restricted area of the brain known as focal cortical dysplasia (FCD). In particular, somatic mutations affecting genes in the mammalian target of rapamycin (mTOR) signaling pathway are highly associated with FCD. Recently, mutations in the mTOR regulatory genes encoding the GATOR1 complex e.g., DEPDC5, NPRL2, NPLR3, have been associated with FCD. While GATOR1 is known to modulate mTOR signaling in response to cellular amino acid levels in non-neuronal systems, to date, no studies have investigated the functional role for these genes in neurons or during brain development. Thus, in Aim 1, we will define the effects of GATOR1 subunit knockdown (KD) on cell size and cell migration and assess whether these effects are mTOR dependent. In Aim 2, we investigate the functional roles of GATOR1 in protein synthesis, subcellular localization, and neuronal excitability. In Aim 3, we assess how GATOR1 KD alters cerebral cortical lamination and generate a new mouse model of FCD. We will show that FCD in this model can be prevented with mTOR inhibitors. These studies will help to understand the role of GATOR1 during in cortical development and provide pre-clinical assessment of mTOR inhibitors for possible future use in GATOR1-associated epilepsies.