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Cell-type specific modulation of NMDA receptors triggers antidepressant actions

Authors :
Golam M. I. Chowdhury
Gerard Sanacora
Danielle M. Gerhard
Ronald S. Duman
Taro Kato
Rong-Jian Liu
Alexa-Nicole Sliby
Kevin L. Behar
Pradeep Banerjee
Ryota Shinohara
Santosh Pothula
Min Wu
Source :
Molecular Psychiatry. 26:5097-5111
Publication Year :
2020
Publisher :
Springer Science and Business Media LLC, 2020.

Abstract

Both the NMDA receptor (NMDAR) positive allosteric modulator (PAM), and antagonist, can exert rapid antidepressant effects as shown in several animal and human studies. However, how this bidirectional modulation of NMDARs causes similar antidepressant effects remains unknown. Notably, the initial cellular trigger, specific cell-type(s), and subunit(s) of NMDARs mediating the antidepressant-like effects of a PAM or an antagonist have not been identified. Here, we used electrophysiology, microdialysis, and NMR spectroscopy to evaluate the effect of a NMDAR PAM (rapastinel) or NMDAR antagonist, ketamine on NMDAR function and disinhibition-mediated glutamate release. Further, we used cell-type specific knockdown (KD), pharmacological, and behavioral approaches to dissect the cell-type specific role of GluN2B, GluN2A, and dopamine receptor subunits in the actions of NMDAR PAM vs. antagonists. We demonstrate that rapastinel directly enhances NMDAR activity on principal glutamatergic neurons in medial prefrontal cortex (mPFC) without any effect on glutamate efflux, while ketamine blocks NMDAR on GABA interneurons to cause glutamate efflux and indirect activation of excitatory synapses. Behavioral studies using cell-type-specific KD in mPFC demonstrate that NMDAR-GluN2B KD on Camk2a- but not Gad1-expressing neurons blocks the antidepressant effects of rapastinel. In contrast, GluN2B KD on Gad1- but not Camk2a-expressing neurons blocks the actions of ketamine. The results also demonstrate that Drd1-expressing pyramidal neurons in mPFC mediate the rapid antidepressant actions of ketamine and rapastinel. Together, these results demonstrate unique initial cellular triggers as well as converging effects on Drd1-pyramidal cell signaling that underlie the antidepressant actions of NMDAR-positive modulation vs. NMDAR blockade.

Details

ISSN :
14765578 and 13594184
Volume :
26
Database :
OpenAIRE
Journal :
Molecular Psychiatry
Accession number :
edsair.doi...........e03e141cf0ebcc1b40db308e27626af8
Full Text :
https://doi.org/10.1038/s41380-020-0796-3