POSTPONED Deconstructing the molecular logic of neural circuit formation: One molecule at a time

Status: This talk is in preparation - details may change
Status: This talk has been cancelled

The brain processes information in millions of neural circuits that operate in parallel or in an interleaved fashion. Neural circuits in turn process information by transmitting and computing signals at synapses. Neural circuit computations critically depend not only on the number and location of synapses between the neurons, but also on the properties of these synapses that can exhibit a wide range of reliability and plasticity. We hypothesize that the construction of neural circuits, mediated by formation of defined synapses, is based on a molecular logic which can serve to explain unitary principles by which the brain processes information. Moreover, we posit that the number, location, and properties of synapses are determined by interactions between pre- and postsynaptic recognition and signaling molecules, and we thus refer to the rules by which these molecules construct circuits as the molecular logic of neural circuits. Several cell-surface and signaling molecules contributing to the molecular logic of neural circuits have been characterized, most prominently presynaptic neurexin adhesion molecules and their various postsynaptic ligands, including neuroligins and cerebellins. Although neuropsychiatric disorders such as autism and schizophrenia are poorly understood, recent progress in human genetics, revolutionized by advances in sequencing technologies, have identified mutations in a large number of genes that predispose to autism and schizophrenia. No common theme unites the affected genes, but a subset of these genes encodes proteins that function at the synapse, including notably the neurexins. We thus further hypothesize that at least a subset of autism and schizophrenia syndromes are produced by specific impairments in the molecular logic of neural circuits, such that the input/output relations in particular circuits are shifted but not blocked, resulting in a skewed information processing capacity of the brain for a selected set of tasks. In support of this hypothesis, we observed that specific autism- and schizophrenia-associated gene mutations in neurexins and their ligands cause selective alterations in a subset of synapses and circuits that induce discrete specific behavioral abnormalities. Although the analysis of the molecular logic of neural circuits and of its impairment in neuropsychiatric disorders is only beginning, the conceptual framework that we outlined above might allow a better understanding of how the brain processes information and of how such information processing becomes altered in autism and schizophrenia.