Group II metabotropic glutamate receptor agonist LY379268 regulates AMPA receptor trafficking in prefrontal cortical neurons
Authors: Yan-Chun Li
Melissa A Snyder
Huaixing Wang
Min-Juan Wang
Wen-Jun Gao
Feng Li
Journal: PLoS ONE (2013)
Discipline: Multidisciplinary
Keywords: mGluR; AMPA receptor; GluA1; GluA2; PSD95
Affiliations: Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.

Abstract:  Group II metabotropic glutamate receptor (mGluR) agonists have emerged as potential treatment drugs for schizophrenia and other neurological disorders, whereas the mechanisms involved remain elusive. Here we examined the effects of LY379268 (LY37) on the expression and trafficking of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor subunits GluA1 and GluA2 in prefrontal neurons. We show that LY37 significantly increased the surface and total expression of both GluA1 and GluA2 subunits in cultured prefrontal neurons and in vivo. This effect was mimicked by the selective mGluR2 agonist LY395756 and was blocked by mGluR2/3 antagonist LY341495. Moreover, we found that both GluA1 and GluA2 subunits were colocalized with PSD95 but not synapsin I, suggesting a postsynaptic localization. Consistently, treatment with LY37 significantly increased the amplitude, but not frequency, of miniature excitatory postsynaptic currents. Further, actinomycin-D blocked LY37's effects, suggesting a transcriptional regulation. In addition, application of glycogen synthase kinase-3beta (GSK-3β) inhibitor completely blocked LY37's effect on GluA2 surface expression, whereas GSK-3β inhibitor itself induced decreases in the surface and total protein levels of GluA1, but not GluA2 subunits. This suggests that GSK-3β differentially mediates GluA1 and GluA2 trafficking. Further, LY37 significantly increased the phosphorylation, but not total protein, of extracellular signal-regulated kinase 1/2 (ERK1/2). Neither ERK1/2 inhibitor PD98059 alone nor PD98059 combined with LY37 treatment induced changes in GluA1 or GluA2 surface expression or total protein levels. Our data thus suggest that mGluR2/3 agonist regulates postsynaptic AMPA receptors by affecting the synaptic trafficking of both GluA1 and GluA2 subunits and that the regulation is likely through ERK1/2 signaling in GluA1 and/or both ERK1/2 and GSK-3β signaling pathways in the GluA2 subunit. 

Retracted: No

PubPeer comments:
 Figure 1. * Red boxes: the bottom two zoomed-in panels appear to look the same while the zoomed-out panels they belong to, look different. Could the authors please check? This was reported to the journal in 2015, with a friendly reminder in 2016, but never addressed. ![file] , 
 #1 Thank you for pointing out the error and we apologize the mistake. Sorry, we did not notice this website. In fact, we addressed this mistake by sending a correction request to the editorial office directly on March 31, 2017. Here I post it again.![file] Correction: Group II metabotropic glutamate receptor agonist LY379268 regulates AMPA receptor trafficking in prefrontal cortical neurons. Min-Juan Wang, Yan-Chun Li, Melissa A. Snyder, Huai-Xing Wang, Feng Li*, Wen-Jun Gao* Published: PLoS One. 2013 Apr 12;8(4):e61787. doi: 10.1371 journal.pone.0061787. Print 2013. In the original Figure 1, it appears that the focused region for LY37 (10 u00b5M) is a duplicate of the focused region for LY37 (100 u00b5M). Here we correct the cropped area of the higher magnification for the LY37 (100 u00b5M). We apologize for the mistake and inconvenience for the readers. ![](http: ) Figure 1. The mGluR2 3 agonist LY37 induces a significant increase in surface expression of GluA1 subunits in cultured PFC neurons. (A) Representative immunofluorescent images of GluA1 receptor surface expression in response to a 60 min exposure to 0.1, 1, 10 or 100 u00b5M LY37 treatment. LY37 at doses of 1, 10 and 100 u00b5M increased the surface expression, i.e., cluster density, of GluA1 subunits on the dendrites. Images were taken by a microscope at 63u00d7oil lens. Scale baru200a=u200a10 u00b5m for upper panels and for the enlarged images in the lower panels. (B) Pooled data show that surface puncta density of GluA1 was significantly increased by LY37 at doses of 1.0 to 100 u00b5M (nu200a=u200a20 neurons for control and for each dose, * p 0.05, ** p 0.01; ANOVA Fu200a=u200a3.501, p 0.01). Reference: 1.tMin-Juan Wang, Yan-Chun Li, Melissa A. Snyder, Huai-Xing Wang, Feng Li*, Wen-Jun Gao* (2013) Group II metabotropic glutamate receptor agonist LY379268 regulates AMPA receptor trafficking in prefrontal cortical neurons. PLOS ONE 8(4):e61787 PMID:23593498 PMCID:PMC3625159 ![file] ,