, 2013) that are still being improved upon. It is also possible to study the function of one or several genes or gene variants against diverse isogenic background from individuals with no known brain disorder as well as “rescue” patient-derived cells by engineering risk variant out of their cells. For all this promise, there

is a long distance to travel before cell-based systems are optimized as complements to carefully interpreted animal models. The ability to differentiate fibroblasts, iPS cells, or hESC cells into diverse mature neurons and glia remains at an early stage, although significant progress is being made (Son et al., 2011, Rouaux and Arlotta, 2013 and Maroof et al., 2013). In addition, technologies needed to compare cultured neurons made by different methods with postmortem human neurons, such as single-cell RNA sequencing or single-cell proteomics, are at different and often early stages

MK 8776 of development. For schizophrenia, both cortical pyramidal neurons and certain parvalbumin-expressing interneurons have been implicated in the disease process (Lewis and Sweet, 2009); however, for essentially all neuropsychiatric disorders, including schizophrenia, the relevant cell types to be modeled remain poorly understood (see below). Another challenge, based on the importance of synaptic proteins, described above, in autism and schizophrenia, will be the ability to make replicable and robust small neural circuits in vitro. Such hurdles notwithstanding, the ability to make http://www.selleckchem.com/products/17-AAG(Geldanamycin).html human neurons in vitro is likely to prove a critically important approach to the study of disease. Insights into the etiology of an illness often arise when science identifies the specific cell populations in which a disease process begins. Such insights would be of enormous value in schizophrenia, bipolar disorder, and autism, in which the culpable cell populations and

circuits are not yet known. Genetics may be particularly valuable in distinguishing phenomena that are causal from phenomena that are mere markers for disease progression or biological accommodations to the disease state: since the genetic alleles existed long before the pathology itself, their association to phenotypes must reflect a directional effect on disease processes rather than a response to them. PDK4 We believe that an important direction in leveraging emerging genetic results in polygenic disease is to use them to find the cell types that matter to each disorder. We propose three ways in which this will be possible. First, some of the implicated genes may have patterns of expression that localize their effects to specific cell populations. Second, regulatory variants may act in geographically restricted ways, altering the expression level in some but not all of the cell populations in which a gene is expressed. Third, some populations of cells may show selective vulnerability to a genetic perturbation, manifesting a difference in cell state.