PMID- 34038186
OWN - NLM
STAT- MEDLINE
DCOM- 20220118
LR  - 20220118
IS  - 1522-1598 (Electronic)
IS  - 0022-3077 (Print)
IS  - 0022-3077 (Linking)
VI  - 126
IP  - 1
DP  - 2021 Jul 1
TI  - Increased excitation-inhibition balance and loss of GABAergic synapses in the 
      serine racemase knockout model of NMDA receptor hypofunction.
PG  - 11-27
LID - 10.1152/jn.00661.2020 [doi]
AB  - There is substantial evidence that both N-methyl-D-aspartate receptor (NMDAR) 
      hypofunction and dysfunction of GABAergic neurotransmission contribute to 
      schizophrenia, though the relationship between these pathophysiological processes 
      remains largely unknown. Although models using cell-type-specific genetic 
      deletion of NMDARs have been informative, they display overly pronounced 
      phenotypes extending beyond those of schizophrenia. Here, we used the serine 
      racemase knockout (SRKO) mice, a model of reduced NMDAR activity rather than 
      complete receptor elimination, to examine the link between NMDAR hypofunction and 
      decreased GABAergic inhibition. The SRKO mice, in which there is a >90% reduction 
      in the NMDAR coagonist d-serine, exhibit many of the neurochemical and behavioral 
      abnormalities observed in schizophrenia. We found a significant reduction in 
      inhibitory synapses onto CA1 pyramidal neurons in the SRKO mice. This reduction 
      increases the excitation/inhibition balance resulting in enhanced synaptically 
      driven neuronal excitability without changes in intrinsic excitability. 
      Consistently, significant reductions in inhibitory synapse density in CA1 were 
      observed by immunohistochemistry. We further show, using a single-neuron genetic 
      deletion approach, that the loss of GABAergic synapses onto pyramidal neurons 
      observed in the SRKO mice is driven in a cell-autonomous manner following the 
      deletion of SR in individual CA1 pyramidal cells. These results support a model 
      whereby NMDAR hypofunction in pyramidal cells disrupts GABAergic synapses leading 
      to disrupted feedback inhibition and impaired neuronal synchrony.NEW & NOTEWORTHY 
      Recently, disruption of excitation/inhibition (E/I) balance has become an area of 
      considerable interest for psychiatric research. Here, we report a reduction in 
      inhibition in the serine racemase knockout mouse model of schizophrenia that 
      increases E/I balance and enhances synaptically driven neuronal excitability. 
      This reduced inhibition was driven cell-autonomously in pyramidal cells lacking 
      serine racemase, suggesting a novel mechanism for how chronic NMDA receptor 
      hypofunction can disrupt information processing in schizophrenia.
FAU - Jami, Shekib A
AU  - Jami SA
AUID- ORCID: 0000-0001-5478-1963
AD  - Center for Neuroscience, University of California, Davis, California.
FAU - Cameron, Scott
AU  - Cameron S
AD  - Center for Neuroscience, University of California, Davis, California.
FAU - Wong, Jonathan M
AU  - Wong JM
AD  - Center for Neuroscience, University of California, Davis, California.
FAU - Daly, Emily R
AU  - Daly ER
AD  - Center for Neuroscience, University of California, Davis, California.
FAU - McAllister, A Kimberley
AU  - McAllister AK
AD  - Center for Neuroscience, University of California, Davis, California.
AD  - Department of Neurobiology, Physiology, and Behavior, University of California, 
      Davis, California.
AD  - Department of Neurology, University of California, Davis, California.
FAU - Gray, John A
AU  - Gray JA
AUID- ORCID: 0000-0002-7287-0748
AD  - Center for Neuroscience, University of California, Davis, California.
AD  - Department of Neurology, University of California, Davis, California.
LA  - eng
GR  - R01 MH117130/MH/NIMH NIH HHS/United States
GR  - R21 MH116315/MH/NIMH NIH HHS/United States
GR  - R01 NS060125/NS/NINDS NIH HHS/United States
PT  - Journal Article
DEP - 20210526
PL  - United States
TA  - J Neurophysiol
JT  - Journal of neurophysiology
JID - 0375404
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - EC 5.1.- (Racemases and Epimerases)
RN  - EC 5.1.1.16 (serine racemase)
SB  - IM
MH  - Animals
MH  - Excitatory Postsynaptic Potentials/*physiology
MH  - Female
MH  - GABAergic Neurons/*metabolism
MH  - Hippocampus/metabolism
MH  - Inhibitory Postsynaptic Potentials/*physiology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Organ Culture Techniques
MH  - Racemases and Epimerases/*deficiency/genetics
MH  - Receptors, N-Methyl-D-Aspartate/*deficiency/genetics
MH  - Schizophrenia/genetics/metabolism
MH  - Synapses/genetics/*metabolism
PMC - PMC8325603
OTO - NOTNLM
OT  - E/I balance
OT  - GABA
OT  - NMDA receptor
OT  - SRR
OT  - inhibition
COIS- No conflicts of interest, financial or otherwise, are declared by the authors.
EDAT- 2021/05/27 06:00
MHDA- 2022/01/19 06:00
PMCR- 2021/05/26
CRDT- 2021/05/26 17:18
PHST- 2021/05/27 06:00 [pubmed]
PHST- 2022/01/19 06:00 [medline]
PHST- 2021/05/26 17:18 [entrez]
PHST- 2021/05/26 00:00 [pmc-release]
AID - JN-00661-2020 [pii]
AID - 10.1152/jn.00661.2020 [doi]
PST - ppublish
SO  - J Neurophysiol. 2021 Jul 1;126(1):11-27. doi: 10.1152/jn.00661.2020. Epub 2021 
      May 26.