Multiple lines of evidence implicate dysfunction of cerebral cortical inhibitory interneurons in the symptomatology of major neuropsychiatric illnesses, including schizophrenia, autism, Tourette disorder, bipolar disorder, and epilepsy. This dysfunction involves subtypes of interneurons that differ in their neurochemistry, connectivity, and physiological characteristics. Recent advances in the derivation of interneurons from human pluripotent stem cells (PSCs) demonstrate their utility in studies of neuronal developmental genetics, function, and disease. Unfortunately, there has been limited success at generating the parvalbumin-expressing, fast- spiking (PV-FS) subgroup, even though this is the most plentiful subgroup of cortical interneuron and their dysfunction is strongly implicated neuropsychiatric disease. Despite tremendous progress in enriching for mouse embryonic stem cell (mESC)-derived PV-FS interneurons, no approach for enriching for their human counterparts is available. This shortfall may be secondary to the length and complexity of human forebrain neural subtype-specific directed differentiation protocols, but also to the protracted maturation of PV-FS cells that normally require strong excitatory inputs to mature. The goal of this highly focused, 3-year, modular budget, renewal application is to build directly upon our substantial progress in deriving PV-FS from mESCs the previous grant cycle, together with our progress at accelerating the maturation of human stem cell derived interneuron-like cells by conditional activation of mTOR signaling, to enrich for the derivation of PV-FS interneurons from human PSCs. Through this scalable process we will also establish experimental systems, including co-culture with prenatal rat cortical neurons and astrocytes, transplantation into neonatal mouse neocortex, and engraftment into human forebrain organoids, that will enable complimentary scientific questions to be addressed. Success in this endeavor will make possible a host of future studies on the etiology, prevention, and treatment of interneuron-related neuropsychiatric disease.
Multiple lines of evidence implicate dysfunction of cerebral cortical inhibitory interneurons in the symptomatology of major neuropsychiatric illnesses. Human stem cell derived neurons have become an invaluable resource for the study and treatment of brain disease, but thus far it has not been possible to enrich for the generation of the most frequently disease associated subclass of cortical interneuron, the parvalbumin expressing fast-spiking cell. This renewal application builds on our recent progress, both in the generation of parvalbumin-expressing fast-spiking interneurons from mouse stem cells, and in the acceleration of human stem cell derived interneuron maturation, to create scalable approaches for the generation of this critical neuronal subclass from human stem cells.
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