PMID- 30275542
OWN - NLM
STAT- MEDLINE
DCOM- 20190110
LR  - 20190110
IS  - 2041-1723 (Electronic)
IS  - 2041-1723 (Linking)
VI  - 9
IP  - 1
DP  - 2018 Oct 1
TI  - Higher ambient synaptic glutamate at inhibitory versus excitatory neurons 
      differentially impacts NMDA receptor activity.
PG  - 4000
LID - 10.1038/s41467-018-06512-7 [doi]
LID - 4000
AB  - Selective disruption of synaptic drive to inhibitory neurons could contribute to 
      the pathophysiology of various brain disorders. We have previously identified a 
      GluN2A-selective positive allosteric modulator, GNE-8324, that selectively 
      enhances N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic responses in 
      inhibitory but not excitatory neurons. Here, we demonstrate that differences in 
      NMDAR subunit composition do not underlie this selective potentiation. Rather, a 
      higher ambient glutamate level in the synaptic cleft of excitatory synapses on 
      inhibitory neurons is a key factor. We show that increasing expression of 
      glutamate transporter 1 (GLT-1) eliminates GNE-8324 potentiation in inhibitory 
      neurons, while decreasing GLT-1 activity enables potentiation in excitatory 
      neurons. Our results reveal an unsuspected difference between excitatory synapses 
      onto different neuronal types, and a more prominent activation of synaptic NMDARs 
      by ambient glutamate in inhibitory than excitatory neurons. This difference has 
      implications for tonic NMDAR activity/signaling and the selective modulation of 
      inhibitory neuron activity to treat brain disorders.
FAU - Yao, Lulu
AU  - Yao L
AD  - School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate 
      School, 518055, Shenzhen, China.
FAU - Grand, Teddy
AU  - Grand T
AD  - Institut de Biologie de l'Ecole Normale Superieure (IBENS), Ecole Normale 
      Superieure, CNRS, INSERM, Universite PSL, 46 rue d'Ulm, 75005, Paris, France.
FAU - Hanson, Jesse E
AU  - Hanson JE
AD  - Department of Neuroscience, Genentech, Inc., South San Francisco, 94080, CA, USA.
FAU - Paoletti, Pierre
AU  - Paoletti P
AD  - Institut de Biologie de l'Ecole Normale Superieure (IBENS), Ecole Normale 
      Superieure, CNRS, INSERM, Universite PSL, 46 rue d'Ulm, 75005, Paris, France.
FAU - Zhou, Qiang
AU  - Zhou Q
AD  - School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate 
      School, 518055, Shenzhen, China. zhouqiang@pkusz.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20181001
PL  - England
TA  - Nat Commun
JT  - Nature communications
JID - 101528555
RN  - 0 (Excitatory Amino Acid Agents)
RN  - 0 (Excitatory Amino Acid Transporter 2)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 3KX376GY7L (Glutamic Acid)
RN  - VH92ICR8HX (N-methyl D-aspartate receptor subtype 2A)
SB  - IM
EIN - Nat Commun. 2018 Nov 15;9(1):4887. PMID: 30442888
MH  - Allosteric Regulation
MH  - Animals
MH  - Excitatory Amino Acid Agents/pharmacology
MH  - Excitatory Amino Acid Transporter 2/genetics/metabolism
MH  - Excitatory Postsynaptic Potentials/drug effects/physiology
MH  - Gene Expression
MH  - Glutamic Acid/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Neurons/drug effects/*physiology
MH  - Receptors, N-Methyl-D-Aspartate/agonists/*metabolism
MH  - Signal Transduction/drug effects/physiology
MH  - Synapses/*metabolism
PMC - PMC6167324
COIS- The authors declare no competing interests.
EDAT- 2018/10/03 06:00
MHDA- 2019/01/11 06:00
PMCR- 2018/10/01
CRDT- 2018/10/03 06:00
PHST- 2018/02/05 00:00 [received]
PHST- 2018/08/31 00:00 [accepted]
PHST- 2018/10/03 06:00 [entrez]
PHST- 2018/10/03 06:00 [pubmed]
PHST- 2019/01/11 06:00 [medline]
PHST- 2018/10/01 00:00 [pmc-release]
AID - 10.1038/s41467-018-06512-7 [pii]
AID - 6512 [pii]
AID - 10.1038/s41467-018-06512-7 [doi]
PST - epublish
SO  - Nat Commun. 2018 Oct 1;9(1):4000. doi: 10.1038/s41467-018-06512-7.