Project Summary Low-dose NMDAR antagonists, including ketamine, elicit rapid antidepressant responses in patients with Major Depressive Disorder (MDD) and in preclinical rodent models, although the efficacy is variable between mechanistically different NMDAR antagonists. These antidepressant effects are proposed to be triggered by either blocking NMDARs on fast spiking parvalbumin basket cells (PV BCs) or on pyramidal cells, but this remains unclear. No studies to date have examined the most immediate effects on the excitation/inhibition balance in hippocampus and prefrontal cortex, brain regions negatively impacted by depression. Using electrophysiological recordings, this proposal will examine the effects of three mechanistically different NMDAR antagonists: ketamine, a non-competitive antagonist, glyx-13, a partial antagonist, and Ro 25-6981, a GluN2B subunit selective antagonist, all of which have antidepressant effects at low dose. Proposed experiments will examine whether NMDAR antagonists decrease interneuron excitability that disinhibits pyramidal cells or whether direct blockade of NMDARs on pyramidal cells trigger the immediate circuit changes. Additionally, pharmacological and genetic approaches will be used to identify how excitability of different interneuron subtypes is modulated by NMDAR antagonists. The goals of the proposal are to identify the location of the NMDARs mediating the rapid effects on key synaptic circuits, and to test whether mechanistically different NMDAR antagonists have shared or distinct effects on the excitation/inhibition balance, which could potentially provide a mechanistic understanding of the lower efficacy of GluN2B-selective NMDAR antagonists in treating depression. Knowledge of how NMDAR antagonists change synaptic circuit dynamics in brain regions involved in MDD may help identify novel targets for future therapeutics.