ABSTRACT Tuberous sclerosis complex (TSC) is a complex genetic disorder that commonly leads to intractable epilepsies, cognitive dysfunction and autism. These clinical features are associated with cortical malformations and neuron overgrowth. The underlying molecular mechanisms are only partially understood, but essentially all cases of TSC are linked to mutations in the TSC1 and TSC2 genes. In normal cells, TSC1 and 2 form a complex that represses the mTOR Complex 1 (mTORC1) signaling pathway, a master regulatory of cell growth. Loss-of-function mutations in TSC1 or 2 lead to mTORC1 hyper-activation, which is considered the primary driver of disease. It is less clear how mechanisms downstream of mTORC1 are involved in TSC pathology. Recent evidence suggests a critical role for deregulation of mRNA translation, but which mRNAs are deregulated and what molecular mechanisms control them are poorly understood. We previously showed that mTORC1 primarily controls the translation of hundreds of mRNAs that are defined by terminal oligopyrimidine (TOP) motifs. More recently, we found that these are controlled through a translation repressor called La-related protein 1 (LARP1). In this study, we propose to use a combination of RNA-seq and bioinformatic strategies to first map the mTORC1-regulated translation landscape of normal and TSC primary mouse cortical neurons, and determine which mRNAs are controlled through LARP1-dependent and independent mechanisms (Aim 1). We will then determine in mice whether inactivation of LARP1 promotes neurodevelopmental phenotypes that characterize TSC, including cortical neuron misplacement and neuron overgrowth (Aim 2). Completion of these aims will comprehensively identify mRNAs whose translation is deregulated in TSC, and test our hypothesis that deregulated translation of TOP mRNAs is a primary driver of TSC pathology. These insights will clarify our understanding of the mechanisms that give rise to TSC pathology in the brain, guiding the development of more effective therapies. They are also likely relevant to understanding other neurologic disorders associated with mTORC1 hyper-activation, including a spectrum of familial epilepsies.