Research in our laboratory uses approaches at the intersection of chemical biology and stem cell biology in order to study cellular pathways relevant to neuropsychiatric disorders. A major focus of the lab involves the identification of cellular disease signatures for schizophrenia and bipolar disorder using patient-derived neurons generated from induced pluripotent stem cells (iPSCs). We differentiate iPSCs to cortical neurons and study differences in synaptic and dendritic spine biology in specific cortical neuron subtypes. We also generate three-dimensional cerebral organoids from the patient-derived iPSCs in order to undertake transcriptomic analyses, studies of mitochondrial function and investigations of neural activity using multi-electrode arrays. In addition to studies under basal conditions, we undertake experiments in the presence of perturbations with sets of annotated small molecules, in order to uncover disease-related vulnerabilities in specific pathways. We couple these perturbations with phosphoproteomic, metabolomic and gene-expression studies to identify cellular pathways that are aberrant in disease. We are also interested in developing new small-molecule potentiators of neuronal activity-dependent induction of Arc (Activity-regulated cytoskeleton-associated protein; Arg3.1) and investigate their effects on synaptic biology in human cortical neurons, in order to develop small molecules with pro-cognitive potential. Another project in the laboratory includes the study of how inflammation affects neurodevelopment. We grow human cerebral organoids to the nine-month stage while exposing them to specific inflammatory cytokines during defined time periods to delineate the temporal effects of inflammatory mediators on cell type-specific gene expression using scRNA-seq and functional effects on neural network activity using multi-electrode arrays.
Rakesh Karmacharya, MD, PhD
Associate Professor of Psychiatry, Harvard Medical School
Investigating the Neurobiology of Psychiatric Diseases Using Patient-Derived Stem Cells