TY - JOUR T1 - Complex neurological phenotype in mutant mice lacking <em>Tsc2</em> in excitatory neurons of the developing forebrain JF - eneuro JO - eneuro DO - 10.1523/ENEURO.0046-15.2015 SP - ENEURO.0046-15.2015 AU - Beth Crowell AU - Gum Hwa Lee AU - Ina Nikolaeva AU - Valentina Dal Pozzo AU - Gabriella D'Arcangelo Y1 - 2015/10/02 UR - http://www.eneuro.org/content/early/2015/10/02/ENEURO.0046-15.2015.abstract N2 - Mutations in the TSC1 and TSC2 genes cause Tuberous Sclerosis Complex, a genetic disease often associated with epilepsy, intellectual disability and autism, and characterized by the presence of anatomical malformations in the brain as well as tumors in other organs. The TSC1 and TSC2 proteins form a complex that inhibits mTORC1 signaling. Previous animal studies demonstrated that Tsc1 or Tsc2 loss of function in the developing brain affects the intrinsic development of neural progenitor cells, neurons or glia. However, the interplay between different cellular elements during brain development was not previously investigated. In this study we generated a novel mutant mouse line (NEX-Tsc2) in which the Tsc2 gene is deleted specifically in postmitotic excitatory neurons of the developing forebrain. Homozygous mutant mice failed to thrive and died prematurely, whereas heterozygous mice appeared normal. Mutant mice exhibited distinct neuroanatomical abnormalities, including malpositioning of selected neuronal populations, neuronal hypertrophy, and cortical astrogliosis. Intrinsic neuronal defects correlated with increased mTORC1 signaling, whereas astrogliosis did not result from altered intrinsic signaling, since these cells were not directly affected by the gene knock out strategy. All neuronal and non-neuronal abnormalities were suppressed by continuous postnatal treatment with the mTORC1 inhibitor RAD001. The data suggest that loss of Tsc2 and mTORC1 signaling activation in excitatory neurons not only disrupts their intrinsic development, but also disrupts the development of cortical astrocytes, likely through the mTORC1-dependent expression of abnormal signaling proteins. This work thus provides new insights into cell-autonomous and non-cell autonomous functions of Tsc2 in brain development.Significance Statement: The Tsc2 protein is defective in most cases of Tuberous Sclerosis Complex (TSC), a disease that causes neurological symptoms and is associated with brain malformations and tumors. Excitatory neurons are the most abundant cell type in the developing embryonic and perinatal brain. To understand how the loss of Tsc2 in these neurons affects overall brain development we generated and characterized a novel conditional mouse mutant line that lacks Tsc2 specifically in developing excitatory neurons of the forebrain. We found that their intrinsic development as well as the development of other cell types such as astroglia is abnormal in mutant mice, suggesting that Tsc2 mutant neurons secrete extracellular signals that disrupt the development of the brain by affecting multiple cell types. ER -