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Ketamine is a well-characterizedN-methyl-D-aspartate receptor (NMDAR) antagonist, although the relevance of this pharmacology to its rapid (within hours of administration) antidepressant actions, which depend on mechanisms convergent with strengthening of excitatory synapses, is unclear. Activation of synaptic NMDARs is necessary for the induction of canonical long-term potentiation (LTP) leading to a sustained expression of increased synaptic strength. We tested the hypothesis that induction of rapid antidepressant effects requires NMDAR activation, by utilizing behavioral pharmacology, western blot quantification of hippocampal synaptoneurosomal protein levels, andex vivohippocampal slice electrophysiology in male mice. We found that ketamine exerts an inverted U-shaped dose-response in antidepressant-sensitive behavioral tests, suggesting that an excessive NMDAR inhibition can prevent ketamine’s antidepressant effects. Ketamine’s actions to induce antidepressant-like behavioral effects, up-regulation of hippocampal AMPAR subunits GluA1 and GluA2, as well as metaplasticity measuredex vivousing electrically-stimulated LTP, were abolished by pretreatment with other non-antidepressant NMDAR antagonists, including MK-801 and CPP. Similarly, the antidepressant-like actions of other putative rapid-acting antidepressant drugs (2R,6R)-hydroxynorketamine (ketamine metabolite), MRK-016 (GABAAα5 negative allosteric modulator), and LY341495 (mGlu2/3receptor antagonist) were blocked by NMDAR inhibition. Ketamine acted synergistically with an NMDAR positive allosteric modulator to exert antidepressant-like behavioral effects and activation of the NMDAR subunit GluN2A was necessary and sufficient for ketamine-like antidepressant-like behavioral effects. We conclude that NMDAR activation is necessary for the beneficial effects of ketamine and other rapid-acting antidepressant compounds. Promoting NMDAR signaling or other approaches that enhance NMDAR-dependent LTP-like synaptic potentiation may be an effective antidepressant strategy.SIGNIFICANCE:The anesthetic and antidepressant drug ketamine is well-characterized as an N-methyl-D-aspartate receptor (NMDAR) antagonist; though, the relevance and full impact of this pharmacology to its antidepressant actions is unclear. We found that NMDAR activation is necessary for the beneficial effects of ketamine and several other putative antidepressant compounds. As such, promoting NMDAR signaling, or other approaches that enhance NMDAR-dependent LTP-like synaptic potentiation in vivo may be an effective antidepressant strategy directly, or acting synergistically with other drug or interventional treatments.

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Diisopropylfluorophosphate (DFP) is a common surrogate for nerve agents used in rodent models of Gulf War Illness (GWI) and is known to alter hippocampal synaptic transmission. Although there has been an increased appreciation for functional differences in the hippocampus between the dorsal (dH) and ventral (vH) sectors, there is a paucity of comparative information characterizing the effects of GWI‐relevant chemicals in the dH and the vH. Our objective was to investigate the effects of acute DFP exposure on hippocampal synaptic transmission using extracellular recording from mouse dH and vH slice preparations. DFP (30 μM) was washed‐in for 30 min while population spike (PS) amplitude was monitored. PS amplitude in the dH and vH was decreased by DFP. Following pretreatment with the nicotinic antagonist mecamylamine (MEC, 30 μM), the DFP‐induced PS inhibition was enhanced in both the dH and vH. In contrast, pretreatment with the muscarinic antagonist atropine (ATR, 3 μM) resulted in DFP enhancement of the PS amplitude in the dH whereas PS inhibition was still observed in the vH. Coapplication of ATR and MEC prevented DFP‐mediated modulation of PS amplitude in the dH but the cholinergic antagonists had no effect on DFP‐mediated PS inhibition in the vH. Similar to ATR pretreatment experiments, dH slices preexposed to the M2 selective antagonist AFDX‐116 (300 nM) exhibited enhanced PS amplitude whereas AFDX‐116 had no effect in the vH. Regarding possible non‐cholinergic mechanisms, DFP has been shown to directly interact with the NMDA receptor (NMDAR). Combined pretreatment with AFDX‐116, MEC, and the competitive NMDAR antagonist D‐APV (25 μM) prevented all DFP‐induced modulation of the PS in both the dH and vH. The AFDX‐116 blockade of the DFP‐mediated PS inhibition in the dH suggests an M2R‐dependent inhibition of excitation in CA1; however, in the vH this DFP effect is primarily mediated by a non‐cholinergic mechanism. Notably, pretreatment with D‐APV alone prevented a decrease in PS amplitude in the dH and the vH, suggesting a common involvement of NMDARs in DFP actions in both hippocampal sectors. Population spike paired‐pulse ratio (PS PPR) was also monitored to assess the impact of DFP exposure on recurrent inhibition. DH and vH slices exposed to DFP exhibited increased PS PPR, consistent with a reduction in inhibitory influence in CA1. Interestingly, in dH and vH slices pretreated with cholinergic antagonists, we still observed a DFP‐mediated increase of PS PPR whereas D‐APV pretreatment alone prevented this increase. Previous reports have demonstrated impairments in hippocampal‐dependent behavioral performance in both animal models and GWI patient populations. Mechanistic distinctions along the septotemporal axis that underlie the actions of DFP on synaptic activity may have important implications for potential therapeutic approaches to the treatment of GWI. Support or Funding Information Department of Defense (to NMF and JJW [Award: W81XWH‐16‐1‐0586]) and UGA Interdisciplinary Toxicology Program (to KAB) Th...