PMID- 32169968
OWN - NLM
STAT- MEDLINE
DCOM- 20200923
LR  - 20201022
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 40
IP  - 17
DP  - 2020 Apr 22
TI  - Nitric Oxide Signaling Strengthens Inhibitory Synapses of Cerebellar Molecular 
      Layer Interneurons through a GABARAP-Dependent Mechanism.
PG  - 3348-3359
LID - 10.1523/JNEUROSCI.2211-19.2020 [doi]
AB  - Nitric oxide (NO) is an important signaling molecule that fulfills diverse 
      functional roles as a neurotransmitter or diffusible second messenger in the 
      developing and adult CNS. Although the impact of NO on different behaviors such 
      as movement, sleep, learning, and memory has been well documented, the identity 
      of its molecular and cellular targets is still an area of ongoing investigation. 
      Here, we identify a novel role for NO in strengthening inhibitory GABA(A) 
      receptor-mediated transmission in molecular layer interneurons of the mouse 
      cerebellum. NO levels are elevated by the activity of neuronal NO synthase (nNOS) 
      following Ca(2+) entry through extrasynaptic NMDA-type ionotropic glutamate 
      receptors (NMDARs). NO activates protein kinase G with the subsequent production 
      of cGMP, which prompts the stimulation of NADPH oxidase and protein kinase C 
      (PKC). The activation of PKC promotes the selective strengthening of 
      alpha3-containing GABA(A)Rs synapses through a GAlphaBetaAlpha receptor-associated 
      protein-dependent mechanism. Given the widespread but cell type-specific 
      expression of the NMDAR/nNOS complex in the mammalian brain, our data suggest 
      that NMDARs may uniquely strengthen inhibitory GABAergic transmission in these 
      cells through a novel NO-mediated pathway.SIGNIFICANCE STATEMENT Long-term 
      changes in the efficacy of GABAergic transmission is mediated by multiple 
      presynaptic and postsynaptic mechanisms. A prominent pathway involves crosstalk 
      between excitatory and inhibitory synapses whereby Ca(2+)-entering through 
      postsynaptic NMDARs promotes the recruitment and strengthening of GABA(A) 
      receptor synapses via Ca(2+)/calmodulin-dependent protein kinase II. Although 
      Ca(2+) transport by NMDARs is also tightly coupled to nNOS activity and NO 
      production, it has yet to be determined whether this pathway affects inhibitory 
      synapses. Here, we show that activation of NMDARs trigger a NO-dependent pathway 
      that strengthens inhibitory GABAergic synapses of cerebellar molecular layer 
      interneurons. Given the widespread expression of NMDARs and nNOS in the mammalian 
      brain, we speculate that NO control of GABAergic synapse efficacy may be more 
      widespread than has been appreciated.
CI  - Copyright (c) 2020 the authors.
FAU - Larson, Erik A
AU  - Larson EA
AD  - Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada 
      H3A 2B4.
AD  - Department of Pharmacology and Therapeutics, McGill University, Montreal H3G 0B1, 
      Quebec, Canada.
FAU - Accardi, Michael V
AU  - Accardi MV
AD  - Graduate Program in Pharmacology, McGill University, Montreal, Quebec, Canada H3G 
      1Y6.
AD  - Department of Pharmacology and Therapeutics, McGill University, Montreal H3G 0B1, 
      Quebec, Canada.
FAU - Wang, Ying
AU  - Wang Y
AD  - Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady 
      Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada 
      R3E 0J9.
AD  - Neuroscience Research Program, Kleysen Institute for Advanced Medicine, Health 
      Sciences Centre, Winnipeg, Manitoba, Canada R3E 3J7.
AD  - The Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba Canada 
      R3E 3P4.
FAU - D'Antoni, Martina
AU  - D'Antoni M
AD  - Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada 
      H3A 2B4.
AD  - Department of Pharmacology and Therapeutics, McGill University, Montreal H3G 0B1, 
      Quebec, Canada.
FAU - Karimi, Benyamin
AU  - Karimi B
AD  - Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady 
      Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada 
      R3E 0J9.
AD  - Neuroscience Research Program, Kleysen Institute for Advanced Medicine, Health 
      Sciences Centre, Winnipeg, Manitoba, Canada R3E 3J7.
AD  - The Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba Canada 
      R3E 3P4.
FAU - Siddiqui, Tabrez J
AU  - Siddiqui TJ
AD  - Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady 
      Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada 
      R3E 0J9.
AD  - Neuroscience Research Program, Kleysen Institute for Advanced Medicine, Health 
      Sciences Centre, Winnipeg, Manitoba, Canada R3E 3J7.
AD  - The Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba Canada 
      R3E 3P4.
FAU - Bowie, Derek
AU  - Bowie D
AUID- ORCID: 0000-0001-9491-8768
AD  - Department of Pharmacology and Therapeutics, McGill University, Montreal H3G 0B1, 
      Quebec, Canada derek.bowie@mcgill.ca.
LA  - eng
GR  - MOP-342247/CIHR/Canada
GR  - MOP-142209/CIHR/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200313
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Excitatory Amino Acid Antagonists)
RN  - 0 (GABARAP protein, mouse)
RN  - 0 (Microtubule-Associated Proteins)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type I)
SB  - IM
MH  - Animals
MH  - Apoptosis Regulatory Proteins/*metabolism
MH  - Cerebellum/drug effects/*metabolism
MH  - Enzyme Inhibitors/pharmacology
MH  - Excitatory Amino Acid Antagonists/pharmacology
MH  - Female
MH  - Interneurons/drug effects/*metabolism
MH  - Male
MH  - Mice
MH  - Microtubule-Associated Proteins/*metabolism
MH  - Neural Inhibition/drug effects/physiology
MH  - Nitric Oxide/*metabolism
MH  - Nitric Oxide Synthase Type I/antagonists & inhibitors
MH  - Patch-Clamp Techniques
MH  - Signal Transduction/drug effects/*physiology
MH  - Synaptic Transmission/drug effects/physiology
PMC - PMC7178912
OTO - NOTNLM
OT  - GABA receptor
OT  - GABARAP
OT  - cerebellum
OT  - electrophysiology
OT  - inhibitory synapse
OT  - plasticity
EDAT- 2020/03/15 06:00
MHDA- 2020/09/24 06:00
PMCR- 2020/10/22
CRDT- 2020/03/15 06:00
PHST- 2019/09/12 00:00 [received]
PHST- 2020/01/13 00:00 [revised]
PHST- 2020/03/03 00:00 [accepted]
PHST- 2020/03/15 06:00 [pubmed]
PHST- 2020/09/24 06:00 [medline]
PHST- 2020/03/15 06:00 [entrez]
PHST- 2020/10/22 00:00 [pmc-release]
AID - JNEUROSCI.2211-19.2020 [pii]
AID - JN-RM-2211-19 [pii]
AID - 10.1523/JNEUROSCI.2211-19.2020 [doi]
PST - ppublish
SO  - J Neurosci. 2020 Apr 22;40(17):3348-3359. doi: 10.1523/JNEUROSCI.2211-19.2020. 
      Epub 2020 Mar 13.