The etiology of many neurodevelopmental disorders remains largely unknown. Although environmental factors may influence their onset, familial studies have shown that schizophrenia, autism, depression, bipolar disorder, and others, all have a variable but strong genetic component. However, candidate genes for these conditions, as identified by genetic linkage analysis and transgenic animal models, can only explain a low percentage of clinical cases. This suggests that important determinants of disease lie elsewhere. Here we propose that epigenetic alterations in the type 3 deiodinase gene (Dio3), either caused by current environmental factors or inherited from previous generations, can lead to brain phenotypes of relevance to neurological disorders. As Dio3 tightly controls thyroid hormone availability across the developing and adult brain, its level of expression is critical to ensure distinct, appropriate levels of thyroid hormone action and normal patterns of gene expression. Dio3 is highly expressed in the central nervous system, and its role in this tissue is likely overlooked in the clinical setting. Clinical diagnosis of thyroid hormone abnormalities is based on serum parameters. However, alterations in Dio3 expression can markedly modify thyroid hormone action in the brain without noticeable changes in the circulating levels of the hormone. In this project, we propose to use several mouse models created or identified in our laboratory that carry genetic and epigenetic alterations affecting the dosage and expression of Dio3 and, thus, the degree of thyroid hormone action in the brain. In these models we will determine several parameters of importance to neurological conditions in humans, such as neonatal and adult patterns of brain gene expression, adult brain morphology and social behavior. In addition, we propose to define the epigenetic footprint of thyroid hormone by analyzing in certain tissues the epigenetic marks that result from developmental overexposure to thyroid hormone. We anticipate demonstrating that Dio3 has an important role for brain development and function and that epigenetic factors affecting Dio3 dosage, de novo or inherited from previous generations, can produce significant neurological phenotypes in genetically intact individuals. This work could have a major impact in our understanding of how susceptibility to neurological conditions can be inherited, highlighting the role of epigenetic information in directly causing disease or triggering it in genetically predisposed individuals. Ultimately, this research may lead to novel epigenetic-based clinical tools for risk assessment, prevention and response to treatment of certain neurological conditions.