Abstract
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.
Highlights
In addition to their prevalence and impact on the individual patient, neurological disorders place a large burden on the world population both in economic impact [1] and emotional toll on families
We explore how induced pluripotent stem cells (iPSCs)-derived neuron technology will help in identifying primary cellular phenotypes associated with neurogenetic disorders, neurodevelopmental disorders, and how these studies might better inform future investigation into pathophysiology and disease treatments and therapies
This paper shows that inhibitory synaptic activity matures more slowly than excitatory synaptic activity and that iPSC-derived neurons can respond to GABA, glutamate, and NMDA application
Summary
In addition to their prevalence and impact on the individual patient, neurological disorders place a large burden on the world population both in economic impact [1] and emotional toll on families. Electrophysiological measurements of iPSC-derived neurons from a mouse model of RTT [69] found similar results, with decreases in AP firing and synaptic activity Both MECP2 duplications as well as deletions result in syndromes with overlapping phenotypes in patients, analogous to the 15q11-q13 region. Studies of human postmortem brain tissue from ASD patients have reported changes in neuron size and number in various regions of neocortex, including prefrontal cortex, a cortical area important for higher-order cognitive processes including social, emotional, and communicative functions [132, 133] Such changes may be the result of deficient activitydependent development of neuronal networks, a process heavily dependent on proper synaptic signaling in early nervous system development. This goal requires a better understanding of the primary pathophysiology of these disorders throughout the earlier stages of development before secondary synaptic deficits accumulate
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