We propose to investigate whether defects in astrocyte maturation and function contribute to the pathophysiology of human neurodevelopmental disorders (NDD) including autism and schizophrenia. Long thought to be primarily passive cells, in recent years, our laboratory and others have found that rodent astrocytes powerfully stimulate both excitatory and inhibitory synapse formation and function (Eroglu and Barres, 2010). Similarly, when human neurons are generated from embryonic or induced pluripotent stem cells (iPSCs), they form few synapses unless astrocytes are present. An emerging theme from recent research is that autism and schizophrenia are diseases of synapses. Could astrocyte defects contribute to the pathophysiology of common devastating NDD? In this application, we will take advantage of iPSC technology to study the development and function of astrocytes derived from iPSCs from patients who have autism and schizophrenia (Ricardo Dolmetsch, our Stanford colleague and collaborator in these studies, will provide these iPSCs). In our first aim, we will characterize and compare the molecular phenotype of human astrocytes generated by iPSCs by established methods to acutely isolated human fetal astrocytes, and then generate improved methods to more quickly generate human astrocytes from iPSCs that more closely resemble the gene profiles of acutely isolated fetal astrocytes from actual human brain tissue. In our second aim, we will characterize the phenotypes of astrocytes derived from iPSC cells from patients with NDD. In our 3rd aim, we will determine whether astrocytes from NDD patients are defective in promoting synapse formation and function. These studies have the potential to shed new light on the neural developmental basis of autism and schizophrenia in humans, have the potential to identify novel astrocyte genes that control synapse formation and function, and will generate new methods and drug testing platforms for human astrocyte generation from iPSCs.
We propose to investigate whether defects in astrocyte maturation and function contribute to the pathophysiology of human neurodevelopmental disorders (NDD) including autism and schizophrenia. We will (1) characterize and compare the molecular phenotype of human astrocytes generated by iPSCs by established methods and new methods we will develop to acutely isolated human fetal astrocytes, (2) characterize the phenotypes of astrocytes derived from iPSC cells from patients with NDD, and (3) determine whether astrocytes from NDD patients are defective in promoting synapse formation and function. These studies will generate new tools to study the role of astrocytes in NDD and have the potential to shed new light on the neural developmental basis of autism and schizophrenia in humans.
