Group II Metabotropic Glutamate Receptor Agonist LY379268 Regulates AMPA Receptor Trafficking in Prefrontal Cortical Neurons

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.

mGluR2/3 agonist LY379268 rescues NMDA and GABAA receptor level deficits induced in a two-hit mouse model of schizophrenia

“…Together with the present results, these findings suggest activating mGluR2/3 receptors could attenuate hypoglutamatergia by increasing the number of active NMDA-R, possibly via the NMDA-R regulating SRC kinase (Trepanier et al, 2013). mGluR2/3 activation has also been shown to increase non-NMDA glutamate receptor levels (Wang et al, 2013), which could contribute to the restoration of GABAA-R binding levels through reduced GABA release (Drew and Vaughan, 2004;Satake et al, 2000). Finally, Gorrie and colleagues have reported that more than 6 h are required for the synthesis of GABAA-R and its integration into the cell membrane (Gorrie et al, 1997), with GABAA-receptors more likely being recycled back into the membrane than replaced with new receptors (Thomas et al, 2005).…”

Glycogen synthase kinase-3 (GSK3): Regulation, actions, and diseases

“…GSK3 has also been reported to regulate dopamine-mediated regulation of cell surface GABA-A (Li et al, 2012) and NMDA (Li et al, 2009b) receptors. AMPA-mediated activity is increased by GSK3 modulating the trafficking of AMPA receptors, in part by phosphorylating guanyl nucleotide dissociation factor (GID), a regulator of Rab5 that mediates endocytosis of AMPA receptors (Wei et al, 2010; Wang et al, 2013). Regulation of kinesin is also likely important in these trafficking actions of GSK3, as GSK3 phosphorylates kinesin light chain 2, which was shown to contribute to the regulation of AMPA receptor trafficking (Morfini et al, 2002; Du et al, 2010).…”

Juvenile treatment with a novel mGluR2 agonist/mGluR3 antagonist compound, LY395756, reverses learning deficits and cognitive flexibility impairments in adults in a neurodevelopmental model of schizophrenia

“…Recent studies have shown that compounds targeting mGluR2/3 are well-tolerated, exhibit few side-effects, and demonstrate a strong potential for alleviating cognitive impairments in both animal models and human subjects with SCZ (Helton et al, 1998; Spooren et al, 2002; Swanson et al, 2005; Fell et al, 2012; Harvey and Shahid, 2012). Specifically, activation of mGluR2/3 can decrease glutamate release pre-synaptically (Schoepp et al, 1999; Cartmell and Schoepp, 2000; Moghaddam, 2004), and simultaneously potentiate NMDAR function post-synaptically (Tyszkiewicz et al, 2004; Xi et al, 2011; Cheng et al, 2013; Trepanier et al, 2013; Wang et al, 2013; Li et al, 2015a; Li et al, 2015b; Engel et al, 2016). …”