COMPARATIVE ASSESSMENT OF SELECTIVE AND PAN-NMDA RECEPTOR SUBTYPE INHIBITION ON FUNCTIONAL CONNECTIVITY IN THE PREFRONTAL CORTEX BY USING AN NR2B NAM AND S-KETAMINE

Depression is characterized by dysfunction of NMDA receptors and an imbalance between excitation and inhibition (E/I imbalance), which is linked to reduced activity in the prefrontal cortex (PFC)—a key region involved in task planning and execution. S-Ketamine, a fast-acting antidepressant, provides rapid relief from depressive symptoms by modulating NMDA signaling and restoring E/I balance. However, its non-selective nature leads to dissociative side effects, potentially stemming from its impact on distinct interneuron (IN) subpopulations.
To address these limitations, we investigated the selective negative allosteric modulator (NAM) BI 1569912 of the NR2B receptor aiming to compare its effects with those of S-Ketamine on prefrontal signal processing, focusing on PV and SST interneurons. Further, we evaluated their contributions to network disinhibition and E/I balance restoration. Whole-cell patch-clamp recordings of excitatory projection neurons were performed to measure sEPSC frequency as a proxy for network activity, optimizing the dose-dependent effects of S-Ketamine. Preliminary results demonstrated that S-Ketamine increased sEPSC frequency, indicating heightened network activity and disinhibition, while the NR2B NAM showed selective modulation of NMDA signaling.
Future investigations will include quantifying and comparing the disinhibitory effects of the NR2B NAM versus S-Ketamine, evaluating their direct inhibitory effects on PV and SST interneurons, and using optogenetic circuit mapping to characterize compound-induced network changes across PFC layers. These findings aim to clarify cell-type-specific and compound-specific mechanisms underlying E/I balance restoration, paving the way for the development of safer and more effective treatments for depression.