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Animal models of neurodevelopmental disorders have provided invaluable insights into the molecular-, cellular-, and circuit-level defects associated with a plethora of genetic disruptions. In many cases, these deficits have been linked to changes in disease-relevant behaviors, but very few of these findings have been translated to treatments for human disease. This may be due to significant species differences and the difficulty in modeling disorders that involve deletion or duplication of multiple genes. The identification of primary underlying pathophysiology in these models is confounded by the accumulation of secondary disease phenotypes in the mature nervous system, as well as potential compensatory mechanisms. The discovery of induced pluripotent stem cell technology now provides a tool to accurately model complex genetic neurogenetic disorders. Using this technique, patient-specific cell lines can be generated and differentiated into specific subtypes of neurons that can be used to identify primary cellular and molecular phenotypes. It is clear that impairments in synaptic structure and function are a common pathophysiology across neurodevelopmental disorders, and electrophysiological analysis at the earliest stages of neuronal development is critical for identifying changes in activity and excitability that can contribute to synaptic dysfunction and identify targets for disease-modifying therapies.

Uncovering True Cellular Phenotypes: Using Induced Pluripotent Stem Cell-Derived Neurons to Study Early Insults in Neurodevelopmental Disorders