PMID- 29793154
OWN - NLM
STAT- MEDLINE
DCOM- 20190220
LR  - 20191210
IS  - 1873-7064 (Electronic)
IS  - 0028-3908 (Print)
IS  - 0028-3908 (Linking)
VI  - 137
DP  - 2018 Jul 15
TI  - Juvenile treatment with mGluR2/3 agonist prevents schizophrenia-like phenotypes 
      in adult by acting through GSK3beta.
PG  - 359-371
LID - S0028-3908(18)30242-9 [pii]
LID - 10.1016/j.neuropharm.2018.05.019 [doi]
AB  - Prodromal memory deficits represent an important marker for the development of 
      schizophrenia (SZ), in which glutamatergic hypofunction occurs in the prefrontal 
      cortex (PFC). The mGluR2/3 agonist LY379268 (LY37) attenuates excitatory 
      N-methyl-D-aspartate receptor (NMDAR)-induced neurotoxicity, a central 
      pathological characteristic of glutamatergic hypofunction. We therefore 
      hypothesized that early treatment with LY37 would rescue cognitive deficits and 
      confer benefits for SZ-like behaviors in adults. To test this, we assessed 
      whether early intervention with LY37 would improve learning outcomes in the 
      Morris Water Maze for rats prenatally exposed to methylazoxymethanol acetate 
      (MAM), a neurodevelopmental SZ model. We found that a medium dose of LY37 
      prevents learning deficits in MAM rats. These effects were mediated through 
      postsynaptic mGluR2/3 via improving GluN2B-NMDAR function by inhibiting glycogen 
      synthase kinase-3beta (GSK3beta). Furthermore, dendritic spine loss and learning and 
      memory deficits observed in adult MAM rats were restored by juvenile LY37 
      treatment, which did not change prefrontal neuronal excitability and 
      glutamatergic synaptic transmission in adult normal rats. Our results provide a 
      mechanism for mGluR2/3 agonists against NMDAR hypofunction, which may prove to be 
      beneficial in the prophylactic treatment of SZ.
CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
FAU - Xing, Bo
AU  - Xing B
AD  - Department of Neurobiology and Anatomy, Drexel University College of Medicine, 
      Philadelphia, 19129, PA, USA.
FAU - Han, Genie
AU  - Han G
AD  - Department of Neurobiology and Anatomy, Drexel University College of Medicine, 
      Philadelphia, 19129, PA, USA.
FAU - Wang, Min-Juan
AU  - Wang MJ
AD  - Department of Neurobiology and Anatomy, Drexel University College of Medicine, 
      Philadelphia, 19129, PA, USA.
FAU - Snyder, Melissa A
AU  - Snyder MA
AD  - Department of Neurobiology and Anatomy, Drexel University College of Medicine, 
      Philadelphia, 19129, PA, USA.
FAU - Gao, Wen-Jun
AU  - Gao WJ
AD  - Department of Neurobiology and Anatomy, Drexel University College of Medicine, 
      Philadelphia, 19129, PA, USA. Electronic address: wg38@drexel.edu.
LA  - eng
GR  - R01 MH085666/MH/NIMH NIH HHS/United States
GR  - R21 MH110678/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 - 20180514
PL  - England
TA  - Neuropharmacology
JT  - Neuropharmacology
JID - 0236217
RN  - 0 (Amino Acids)
RN  - 0 (Antipsychotic Agents)
RN  - 0 (Bridged Bicyclo Compounds, Heterocyclic)
RN  - 0 (Excitatory Amino Acid Agonists)
RN  - 0 (LY 379268)
RN  - 0 (Receptors, Metabotropic Glutamate)
RN  - 0 (metabotropic glutamate receptor 2)
RN  - 0 (metabotropic glutamate receptor 3)
RN  - 592-62-1 (Methylazoxymethanol Acetate)
RN  - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
SB  - IM
MH  - Amino Acids/*pharmacology
MH  - Animals
MH  - Antipsychotic Agents/*pharmacology
MH  - Bridged Bicyclo Compounds, Heterocyclic/*pharmacology
MH  - Dendritic Spines/drug effects/enzymology
MH  - Disease Models, Animal
MH  - Excitatory Amino Acid Agonists/*pharmacology
MH  - Female
MH  - Glycogen Synthase Kinase 3 beta/*metabolism
MH  - Learning Disabilities/drug therapy/enzymology
MH  - Methylazoxymethanol Acetate
MH  - Prefrontal Cortex/drug effects/enzymology
MH  - Pregnancy
MH  - Prenatal Exposure Delayed Effects
MH  - Rats, Sprague-Dawley
MH  - Receptors, Metabotropic Glutamate/agonists/metabolism
MH  - Schizophrenia/*enzymology/*prevention & control
MH  - Tissue Culture Techniques
PMC - PMC6050107
MID - NIHMS969663
OTO - NOTNLM
OT  - Animal model
OT  - NMDA receptor
OT  - Neurodevelopment
OT  - Prefrontal cortex
OT  - Schizophrenia
OT  - mGluR2/3 agonist
COIS- Conflict of Interest The authors declare no competing financial interests.
EDAT- 2018/05/25 06:00
MHDA- 2019/03/21 06:00
PMCR- 2019/07/15
CRDT- 2018/05/25 06:00
PHST- 2018/01/29 00:00 [received]
PHST- 2018/04/22 00:00 [revised]
PHST- 2018/05/12 00:00 [accepted]
PHST- 2018/05/25 06:00 [pubmed]
PHST- 2019/03/21 06:00 [medline]
PHST- 2018/05/25 06:00 [entrez]
PHST- 2019/07/15 00:00 [pmc-release]
AID - S0028-3908(18)30242-9 [pii]
AID - 10.1016/j.neuropharm.2018.05.019 [doi]
PST - ppublish
SO  - Neuropharmacology. 2018 Jul 15;137:359-371. doi: 
      10.1016/j.neuropharm.2018.05.019. Epub 2018 May 14.