PMID- 32488125
OWN - NLM
STAT- MEDLINE
DCOM- 20220131
LR  - 20220606
IS  - 1476-5578 (Electronic)
IS  - 1359-4184 (Linking)
VI  - 26
IP  - 9
DP  - 2021 Sep
TI  - Cell-type specific modulation of NMDA receptors triggers antidepressant actions.
PG  - 5097-5111
LID - 10.1038/s41380-020-0796-3 [doi]
AB  - 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.
CI  - (c) 2020. The Author(s), under exclusive licence to Springer Nature Limited.
FAU - Pothula, Santosh
AU  - Pothula S
AUID- ORCID: 0000-0002-8019-3396
AD  - Department of Psychiatry, Yale School of Medicine, New Haven, CT, 06511, USA. 
      santosh.pothula@yale.edu.
FAU - Kato, Taro
AU  - Kato T
AD  - Department of Psychiatry, Yale School of Medicine, New Haven, CT, 06511, USA.
FAU - Liu, Rong-Jian
AU  - Liu RJ
AD  - Department of Psychiatry, Yale School of Medicine, New Haven, CT, 06511, USA.
FAU - Wu, Min
AU  - Wu M
AD  - Department of Psychiatry, Yale School of Medicine, New Haven, CT, 06511, USA.
FAU - Gerhard, Danielle
AU  - Gerhard D
AD  - Department of Psychiatry, Yale School of Medicine, New Haven, CT, 06511, USA.
AD  - Department of Psychiatry, Weill Cornell Medicine, New York, NY, 10065, USA.
FAU - Shinohara, Ryota
AU  - Shinohara R
AUID- ORCID: 0000-0001-5279-2642
AD  - Department of Psychiatry, Yale School of Medicine, New Haven, CT, 06511, USA.
FAU - Sliby, Alexa-Nicole
AU  - Sliby AN
AD  - Department of Psychiatry, Yale School of Medicine, New Haven, CT, 06511, USA.
FAU - Chowdhury, Golam M I
AU  - Chowdhury GMI
AD  - Department of Psychiatry, Yale School of Medicine, New Haven, CT, 06511, USA.
FAU - Behar, Kevin L
AU  - Behar KL
AD  - Department of Psychiatry, Yale School of Medicine, New Haven, CT, 06511, USA.
FAU - Sanacora, Gerard
AU  - Sanacora G
AD  - Department of Psychiatry, Yale School of Medicine, New Haven, CT, 06511, USA.
FAU - Banerjee, Pradeep
AU  - Banerjee P
AD  - Allergan Inc., Madison, NJ, USA.
FAU - Duman, Ronald S
AU  - Duman RS
AUID- ORCID: 0000-0001-8690-8439
AD  - Department of Psychiatry, Yale School of Medicine, New Haven, CT, 06511, USA.
LA  - eng
GR  - R01 MH093897/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200602
PL  - England
TA  - Mol Psychiatry
JT  - Molecular psychiatry
JID - 9607835
RN  - 0 (Antidepressive Agents)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 690G0D6V8H (Ketamine)
SB  - IM
MH  - Animals
MH  - Antidepressive Agents/pharmacology
MH  - Humans
MH  - Interneurons/metabolism
MH  - *Ketamine/pharmacology
MH  - Prefrontal Cortex/metabolism
MH  - Pyramidal Cells/metabolism
MH  - *Receptors, N-Methyl-D-Aspartate/metabolism
EDAT- 2020/06/04 06:00
MHDA- 2022/02/01 06:00
CRDT- 2020/06/04 06:00
PHST- 2020/04/30 00:00 [received]
PHST- 2020/05/18 00:00 [accepted]
PHST- 2020/05/13 00:00 [revised]
PHST- 2020/06/04 06:00 [pubmed]
PHST- 2022/02/01 06:00 [medline]
PHST- 2020/06/04 06:00 [entrez]
AID - 10.1038/s41380-020-0796-3 [pii]
AID - 10.1038/s41380-020-0796-3 [doi]
PST - ppublish
SO  - Mol Psychiatry. 2021 Sep;26(9):5097-5111. doi: 10.1038/s41380-020-0796-3. Epub 
      2020 Jun 2.