Group I mGluR antagonist rescues the deficit of D1-induced LTP in a mouse model of fragile X syndrome.
BACKGROUND
Fragile X syndrome (FXS) is caused by the absence of the mRNA-binding protein Fragile X mental retardation protein (FMRP), encoded by the Fmr1 gene. Overactive signaling by group 1 metabotropic glutamate receptor (Grp1 mGluR) could contribute to slowed synaptic development and other symptoms of FXS. Our previous study has identified that facilitation of synaptic long-term potentiation (LTP) by D1 receptor is impaired in Fmr1 knockout (KO) mice. However, the contribution of Grp1 mGluR to the facilitation of synaptic plasticity by D1 receptor stimulation in the prefrontal cortex has been less extensively studied.


RESULTS
Here we demonstrated that DL-AP3, a Grp1 mGluR antagonist, rescued LTP facilitation by D1 receptor agonist SKF81297 in Fmr1KO mice. Grp1 mGluR inhibition restored the GluR1-subtype AMPA receptors surface insertion by D1 activation in the cultured Fmr1KO neurons. Simultaneous treatment of Grp1 mGluR antagonist with D1 agonist recovered the D1 receptor signaling by reversing the subcellular redistribution of G protein-coupled receptor kinase 2 (GRK2) in the Fmr1KO neurons. Treatment of SKF81297 alone failed to increase the phosphorylation of NR2B-containing N-methyl D-aspartate receptors (NMDARs) at Tyr-1472 (p-NR2B-Tyr1472) in the cultures from KO mice. However, simultaneous treatment of DL-AP3 could rescue the level of p-NR2B-Tyr1472 by SKF81297 in the cultures from KO mice. Furthermore, behavioral tests indicated that simultaneous treatment of Grp1 mGluR antagonist with D1 agonist inhibited hyperactivity and improved the learning ability in the Fmr1KO mice.


CONCLUSIONS
The findings demonstrate that mGluR1 inhibition is a useful strategy to recover D1 receptor signaling in the Fmr1KO mice, and combination of Grp1 mGluR antagonist and D1 agonist is a potential drug therapy for the FXS.
Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, 17 Changle West Road, Xi'an, 710032, China.
Zhao-Hui
ZH
Xu
Qi
Q
Yang
Bin
B
Feng
Shui-bing
SB
Liu
Nan
N
Zhang
Jiang-hao
JH
Xing
Xiao-Qiang
XQ
Li
Yu-mei
YM
Wu
Guo-Dong
GD
Gao
Ming-Gao
MG
Zhao
D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000378:metabolism; D005600:Fragile X Syndrome / Q000188:drug therapy* / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018091:Receptors, AMPA / Q000502:physiology; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D000409:Alanine; D051860:Fragile X Messenger Ribonucleoprotein 1; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; C497684:Fmr1 protein, mouse; C104077:metabotropic glutamate receptor type 1; C000211:2-amino-3-phosphonopropionic acid