PMID- 37349472
OWN - NLM
STAT- MEDLINE
DCOM- 20231023
LR  - 20231026
IS  - 1740-634X (Electronic)
IS  - 0893-133X (Print)
IS  - 0893-133X (Linking)
VI  - 48
IP  - 12
DP  - 2023 Nov
TI  - Deficits in integrative NMDA receptors caused by Grin1 disruption can be rescued 
      in adulthood.
PG  - 1742-1751
LID - 10.1038/s41386-023-01619-y [doi]
AB  - Glutamatergic NMDA receptors (NMDAR) are critical for cognitive function, and 
      their reduced expression leads to intellectual disability. Since subpopulations 
      of NMDARs exist in distinct subcellular environments, their functioning may be 
      unevenly vulnerable to genetic disruption. Here, we investigate synaptic and 
      extrasynaptic NMDARs on the major output neurons of the prefrontal cortex in mice 
      deficient for the obligate NMDAR subunit encoded by Grin1 and wild-type 
      littermates. With whole-cell recording in brain slices, we find that single, 
      low-intensity stimuli elicit surprisingly-similar glutamatergic synaptic currents 
      in both genotypes. By contrast, clear genotype differences emerge with 
      manipulations that recruit extrasynaptic NMDARs, including stronger, repetitive, 
      or pharmacological stimulation. These results reveal a disproportionate 
      functional deficit of extrasynaptic NMDARs compared to their synaptic 
      counterparts. To probe the repercussions of this deficit, we examine an 
      NMDAR-dependent phenomenon considered a building block of cognitive integration, 
      basal dendrite plateau potentials. Since we find this phenomenon is readily 
      evoked in wild-type but not in Grin1-deficient mice, we ask whether plateau 
      potentials can be restored by an adult intervention to increase Grin1 expression. 
      This genetic manipulation, previously shown to restore cognitive performance in 
      adulthood, successfully rescues electrically-evoked basal dendrite plateau 
      potentials after a lifetime of NMDAR compromise. Taken together, our work 
      demonstrates NMDAR subpopulations are not uniformly vulnerable to the genetic 
      disruption of their obligate subunit. Furthermore, the window for functional 
      rescue of the more-sensitive integrative NMDARs remains open into adulthood.
CI  - (c) 2023. The Author(s).
FAU - Venkatesan, Sridevi
AU  - Venkatesan S
AD  - Department of Physiology, University of Toronto, Toronto, ON, Canada.
FAU - Binko, Mary A
AU  - Binko MA
AD  - Department of Physiology, University of Toronto, Toronto, ON, Canada.
AD  - University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
FAU - Mielnik, Catharine A
AU  - Mielnik CA
AD  - Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, 
      Canada.
FAU - Ramsey, Amy J
AU  - Ramsey AJ
AUID- ORCID: 0000-0002-2717-5279
AD  - Department of Physiology, University of Toronto, Toronto, ON, Canada.
AD  - Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, 
      Canada.
FAU - Lambe, Evelyn K
AU  - Lambe EK
AUID- ORCID: 0000-0002-5994-6090
AD  - Department of Physiology, University of Toronto, Toronto, ON, Canada. 
      evelyn.lambe@utoronto.ca.
AD  - Department of OBGYN, University of Toronto, Toronto, ON, Canada. 
      evelyn.lambe@utoronto.ca.
AD  - Department of Psychiatry, University of Toronto, Toronto, ON, Canada. 
      evelyn.lambe@utoronto.ca.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230622
PL  - England
TA  - Neuropsychopharmacology
JT  - Neuropsychopharmacology : official publication of the American College of 
      Neuropsychopharmacology
JID - 8904907
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
SB  - IM
MH  - Mice
MH  - Animals
MH  - *Receptors, N-Methyl-D-Aspartate/genetics/metabolism
MH  - *Neurons/metabolism
MH  - Prefrontal Cortex/metabolism
MH  - Synapses/metabolism
PMC - PMC10579298
COIS- The authors declare no competing interests.
EDAT- 2023/06/23 01:10
MHDA- 2023/10/23 00:42
PMCR- 2023/06/22
CRDT- 2023/06/22 23:22
PHST- 2022/11/22 00:00 [received]
PHST- 2023/05/22 00:00 [accepted]
PHST- 2023/05/10 00:00 [revised]
PHST- 2023/10/23 00:42 [medline]
PHST- 2023/06/23 01:10 [pubmed]
PHST- 2023/06/22 23:22 [entrez]
PHST- 2023/06/22 00:00 [pmc-release]
AID - 10.1038/s41386-023-01619-y [pii]
AID - 1619 [pii]
AID - 10.1038/s41386-023-01619-y [doi]
PST - ppublish
SO  - Neuropsychopharmacology. 2023 Nov;48(12):1742-1751. doi: 
      10.1038/s41386-023-01619-y. Epub 2023 Jun 22.