Structural plasticity basis of fast-acting antidepressant action

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PROJECT SUMMARY A single subanesthetic dose of ketamine, an N-methyl-D-aspartate receptor antagonist, leads to fast- acting antidepressant effects. In rodent models, systemic ketamine administration is associated with higher dendritic spine density in the frontal cortex, reflecting structural remodeling that could underlie the behavioral changes. However, turnover of dendritic spines is a dynamic process in vivo. The time course and specificity of ketamine's effect on structural plasticity remain unclear. In preliminary studies, we used longitudinal two- photon microscopy to repeatedly visualize the same set of dendritic branches in the mouse medial frontal cortex before and after a single injection of ketamine or saline. Our data suggest that the higher dendritic spine density associated with ketamine administration is driven by an elevated rate of spine formation, and that a fraction of these newly formed spines becomes persistent. But what is special about these added synapses? In this proposal, we will test whether spines form at random or at particular dendritic locations, e.g. preferentially postsynaptic to particular axonal inputs or at sites affected by chronic stress. In Aim 1, we will test whether ketamine preferentially restores thalamocortical synapses. We will adapt a novel viral strategy to label axonal boutons in vivo. We will quantify effects of ketamine on in vivo dendritic spine turnover in the medial frontal cortex, focusing on spines postsynaptic to fluorescently tagged thalamocortical or callosal inputs. In Aim 2, we will test whether ketamine preferentially reverses social stress-induced synaptic deficits. We will characterize the interactive effects of chronic social defeat and ketamine on structural plasticity in the frontal cortex. Completing these aims would link rapidly acting antidepressants to reversals of specific connectivity and stress-induced deficits. Restoration of pathway-specific synapses could be a novel mechanism for antidepressant action that operates at the circuit level.