Dissecting the effect of MTOR somatic mutations in aberrant brain development and neural circuit formation

Abstract

Part I. Brain somatic mutations in MTOR affecting aberrant brain developmentFocal malformations of cortical development (FMCDs) are major etiologies of pediatric intractable epilepsies exhibiting cortical dyslamination. Brain somatic mutations in MTOR have recently been identified as a major genetic cause of FMCDs. However, the molecular mechanism by which these mutations lead to cortical dyslamination remains poorly understood. Here, using patient tissue, genome-edited cells, and mouse models with brain somatic mutations in MTOR, I discovered that disruption of neuronal ciliogenesis by the mutations underlies cortical dyslamination in FMCDs. I found that abnormal accumulation of OFD1 at centriolar satellites due to perturbed autophagy was responsible for the defective neuronal ciliogenesis. Additionally, I found that disrupted neuronal ciliogenesis accounted for cortical dyslamination in FMCDs by compromising Wnt signals essential for neuronal polarization. Altogether, this study describes a molecular mechanism by which brain somatic mutations in MTOR contribute to the pathogenesis of cortical dyslamination in FMCDs.Part II. Brain somatic mutations in MTOR affecting aberrant neural circuit formation In the past, lots of studies in epilepsy have focused on electrical or chemoconvulsants. However, these models couldn’t sufficiently represent the pathophysiology of human epilepsy. FMCDs are highly associated with psychiatric symptoms. Through in utero electroporation in the embryonic mouse brain, epilepsy mice with brain somatic mutations have been modeled. Though behavioral deficits due to hyperactivation of MTOR signaling in conditional mice have been reported, the role of MTOR brain somatic mutation on behavioral phenotype was still elusive. Especially, whether these small population of mutated neurons can change neural circuit formation and, in turn, several behavioral abnormalities has not been explored. Through virus injection and optogenetical modulation, I found that brain somatic mutation in MTOR disrupts neural circuitry, which includes aberrant axonal projection and abnormal neuronal firing, resulting in behavioral abnormalities in FMCDs.