Mitochondrial metabolism of reactive oxygen species (ROS) is tightly regulated during brain development. Imbalance has been correlated to neuropsychiatric disorders. Nevertheless, the contribution of ROS accumulation to aberrant cortical circuit organization and function remains unknown. Individuals with 22q11 deletion syndrome (22q11DS) are highly susceptible to psychiatric disorders; therefore, 22q11DS has been suggested as a model for studying the neurodevelopmental origins of these disorders. Six genes –Mrpl40, Tango2, Prodh, Zdhhc8, Txnrd2 and Scl25a1– located in the 22q11DS commonly deleted region encode proteins that localize to mitochondria. This project aimed to characterize the effects of altered mitochondrial function, due to diminished dosage of these genes, on cortical projection neuron development, using the LgDel mouse model of 22q11DS. I found growth deficits in LgDel neurons that are due to increased mitochondrial ROS and are Txnrd2-dependent. Antioxidant treatment, by n-acetyl cysteine (NAC), rescues neuronal morphogenesis in LgDel and Txnrd2-depleted neurons in vitro and in vivo. Electroporation of Txnrd2 restores ROS levels and normal dendritic and axonal growth. Txnrd2-dependent redox regulation underlies a key aspect of cortical circuit differentiation in a mouse model of 22q11DS. These studies define the effects of mitochondrial accumulation of ROS on neuronal integrity, and establish the role of altered pyramidal neuron differentiation in the formation of circuits in 22q11DS. These data provide novel insight into the role of redox imbalance in aberrant development of cortical circuits.
|Advisor:||LaMantia, Anthony-Samuel, Maynard, Thomas M.|
|Commitee:||Chiaramello, Anne, Manzini, Chiara, O’Halloran, Damien, Sockanathan, Shanthini|
|School:||The George Washington University|
|School Location:||United States -- District of Columbia|
|Source:||DAI-B 79/02(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Neurosciences, Developmental biology|
|Keywords:||Autism, Mitochondria, Neurodevelopment, Neuronal differentiation, Oxidative stress, Schizophrenia|
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