Positive modulation of NMDA receptors by AGN-241751 exerts rapid antidepressant-like effects via excitatory neurons

Abstract

Dysregulation of the glutamatergic system and its receptors in medial prefrontal cortex (mPFC) has been implicated in major depressive disorder. Recent preclinical studies have shown that enhancing NMDA receptor (NMDAR) activity can exert rapid antidepressant-like effects. AGN-241751, an NMDAR positive allosteric modulator (PAM), is currently being tested as an antidepressant in clinical trials, but the mechanism and NMDAR subunit(s) mediating its antidepressant-like effects are unknown. We therefore used molecular, biochemical, and electrophysiological approaches to examine the cell-type-specific role of GluN2B-containing NMDAR in mediating antidepressant-like behavioral effects of AGN-241751. We demonstrate that AGN-241751 exerts antidepressant-like effects and reverses behavioral deficits induced by chronic unpredictable stress in mice. AGN-241751 treatment enhances NMDAR activity of excitatory and parvalbumin-inhibitory neurons in mPFC, activates Akt/mTOR signaling, and increases levels of synaptic proteins crucial for synaptic plasticity in the prefrontal cortex. Furthermore, cell-type-specific knockdown of GluN2B-containing NMDARs in mPFC demonstrates that GluN2B subunits on excitatory, but not inhibitory, neurons are necessary for antidepressant-like effects of AGN-241751. Together, these results demonstrate antidepressant-like actions of the NMDAR PAM AGN-241751 and identify GluN2B on excitatory neurons of mPFC as initial cellular trigger underlying these behavioral effects.

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Fig. 1: AGN-241751 treatment produces dose-dependent antidepressant-like effects and activates Akt/mTOR signaling in the PFC.
Fig. 2: A single dose of AGN-241751 reverses CUS-induced depressive-like behaviors.
Fig. 3: AGN-241751 enhances NMDA-, but not AMPA-mediated, inward currents in excitatory and inhibitory neurons.
Fig. 4: Knockdown of GluN2B in the mPFC of Camk2a-Cre mice prevents antidepressant-like effects of AGN-241751.
Fig. 5: Knockdown of GluN2B in the mPFC of Gad1-Cre mice does not block antidepressant-like effects of AGN-241751.

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Acknowledgements

We thank Xiao Yuan Li for her help with genotyping of mouse lines.

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SP, PB, and RSD designed the study. SP wrote the paper. MRP edited the paper. SP, R-JL, MW, and A-NS conducted experiments, analyzed data, and interpreted the results. All authors reviewed and approved the final paper.

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Correspondence to Santosh Pothula.

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Pothula, S., Liu, RJ., Wu, M. et al. Positive modulation of NMDA receptors by AGN-241751 exerts rapid antidepressant-like effects via excitatory neurons. Neuropsychopharmacol. (2020). https://doi.org/10.1038/s41386-020-00882-7

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