PROJECT SUMMARY Abnormal synapse structure, function, and number are posited to underlie a range of diseases, from neurodevelopmental conditions such as autism to neurodegenerative disorders such as Alzheimer's. Each neuron synapses with functionally diverse upstream and downstream partner neurons to support different computations and facets of behavior, and recently discovered partner-specific synaptic abnormalities are hypothesized to drive conditions such as schizophrenia and Alzheimer's. These observations indicate that the essential subunits of neural information processing are not neurons themselves but their synaptic connections, and that understanding brain function in health and disease will require understanding how different synapses contribute to computations and behavior. In recent years, causal relationships of this sort have been established for identified cell types in neural processing and behavior using chemogenetic and optogenetic tools to manipulate identified neurons, yet these methods lack the spatial resolution necessary to selectively manipulate synaptic connections with specific partners. As a result, there is an outstanding need for methods able to manipulate communication between defined synaptic partners in health and in disease. This proposal describes a solution to this problem, a new technology termed controller locally affecting synaptic partners (CLASP). I explain the underlying concept and how we will implement and rigorously validate CLASP using a sequence of in vitro and in vivo assays. To demonstrate the power of this approach, we will then apply CLASP in vivo to investigate the functional role of a fundamental circuit motif in cortical processing. Finally, I delineate how CLASP can be applied to studies in neurological and psychiatric disease models and to investigate synapse-specific therapeutic interventions, and envision how the CLASP approach could be adapted to create additional variants for synapse-specific manipulations. The successful completion of these studies will yield a transformative new technology and illustrate its power to unravel neural circuits in health and disease with unprecedented specificity.