Interrogating and sculpting synapses and circuits for rapidly acting antidepressant effects

Dendritic spines are the remarkable, highly specialized membrane compartments on neurons that house the postsynaptic, receiving end of most excitatory, glutamatergic synapses in the brain. They are highly plastic and change with learning, in development, and in disease. I am proposing to use novel multiphoton assays I have designed in order to measure how specific disease and therapeutic processes regulate plasticity rules at the level of the synapse and the neural circuit, in genetically defined systems of the mouse brain. In parallel, we will apply genetically targeted proteomic assays to the same circuits, for a broad understanding of synaptic and cellular changes induced by depressive state and rapidly acting antidepressant drugs. The unique synthesis of novel optical microscopy approaches, molecular tools, chemistry, and physiology represents a significant advance over canonical approaches to studying plasticity of neural circuits. The goal is to build a conceptual framework to enable harnessing the genesis of new synapses and the regulation of plasticity for mental health therapeutics. In addition, this work will resolve fundamental mysteries surrounding the genesis of synapses and will develop useful tools for the neuroscience community.