Research in the Karmacharya laboratory uses approaches at the intersection of chemical biology and stem cell biology in order to investigate cellular pathways relevant to neuropsychiatric disorders. A major project in the lab involves the identification of disease signatures for schizophrenia and bipolar disorder using patient-derived neurons generated from induced pluripotent stem cells (iPSCs). We differentiatate iPSCs to cortical neurons and study differences in synaptic and dendritic spine biology in specific cortical neuron subtypes, using super-resolution microscopy as well as high-resolution calcium imaging studies. We undertake studies under basal conditions, as well as in the presence of perturbations with sets of annotated small molecules, in order to uncover disease-related vulnerabilities in specific cellular pathways. We couple these studies with phosphoproteomic, metabolomic and gene-expression studies to delineate the nature of cellular process 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 role that non-histone acetylation of beta-catenin and Akt plays in synaptogenesis. We use small molecule probes to dissect the mechanisms underlying the effect of histone deacetylase 6 (HDAC6) on synaptic stabilization. Finally, we are interested in using small-molecule gene expression databases in order to identify compounds that have potential therapeutic potential. Along this line, we have identified a small molecule whose gene expression profile is strongly anticorrelated to the gene expression profile for Parkinson's Disease and we are undertaking studies in human iPSC-derived dopaminergic neurons to delineate the mechanistic underpinnings of neuroprotection in dopaminergic neurons.