Group II Metabotropic Glutamate Receptor Agonist Ameliorates MK801-Induced Dysfunction of NMDA Receptors via the Akt/GSK-3β Pathway in Adult Rat Prefrontal Cortex

Abstract

Pharmacological intervention targeting mGluRs has emerged as a potential treatment for schizophrenia, whereas the mechanisms involved remain elusive. We explored the antipsychotic effects of a mGluR2/3 agonist in the MK-801 model of schizophrenia in the rat prefrontal cortex. We found that the mGluR2/3 agonist LY379268 effectively recovered the disrupted expression of NMDA receptors induced by MK-801 administration. This effect was attributable to the direct regulatory action of LY379268 on NMDA receptors via activation of the Akt/GSK-3β signaling pathway. As occurs with the antipsychotic drug clozapine, acute treatment with LY379268 significantly increased the expression and phosphorylation of NMDA receptors, as well as Akt and GSK-3β. Physiologically, LY379268 significantly enhanced NMDA-induced current in prefrontal neurons and a GSK-3β inhibitor occluded this effect. In contrast to the widely proposed mechanism of modulating presynaptic glutamate release, our results strongly argue that mGluR2/3 agonists modulate the function of NMDA receptors through postsynaptic actions and reverse the MK-801-induced NMDA dysfunction via the Akt/GSK-3β pathway. This study provides novel evidence for postsynaptic mechanisms of mGluR2/3 in regulation of NMDA receptors and presents useful insights into the mechanistic actions of mGluR2/3 agonists as potential antipsychotic agents for treating schizophrenia.

Gestational Methylazoxymethanol Exposure Leads to NMDAR Dysfunction in Hippocampus During Early Development and Lasting Deficits in Learning

“…Downregulated NMDAR subunits are usually seen in postmortem tissue from schizophrenics (Akbarian et al, 1996;Gao et al, 2000;Kristiansen et al, 2007) and animal models with disrupted NMDAR function that have SZ-like symptoms (Belforte et al, 2010;GunduzBruce, 2009;Lisman et al, 2008;Xi et al, 2011). However, the majority of these experiments has been conducted on postmortem adult human brains or in adult animals and thus does not exclude the possibility that NMDAR expression and function can be differentially regulated over development.…”

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

“…Given the significant effects of mGluR2/3 agonists on NMDAR expression and function in the adult rat PFC (Xi et al, 2011; Li et al, 2015b), one of the major concerns of this undertaking was the potential side effects. However, LY39 did not have significant effects on the expression of NMDAR subunits and limited effects on NMDA-mEPSCs in saline-treated animals (Fig.…”

“…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). …”

GSK3β Hyperactivity during an Early Critical Period Impairs Prefrontal Synaptic Plasticity and Induces Lasting Deficits in Spine Morphology and Working Memory

“…The classification of age group [(newborns on postnatal day (P1) to P7, early juvenile at P14, late juvenile at P21 to P28, adolescence at P45 and young adult at P60] was based on others' (Spear, 2000) and our previous studies (Snyder et al, 2013;Wang and Gao, 2009). Whole cell extracts from medial PFC tissues were processed for Western blot analysis with different antibodies as indicated in our published procedure (Xi et al, 2011).…”

“…There are two mammalian isoforms of GSK3, which are primarily regulated by inhibitory phosphorylation at either Ser21 of GSK3α or Ser 9 for GSK3β. Psychomimetic drugs increase GSK3β activity, whereas antipsychotics result in the inhibition of GSK3β by altering pGSK3βSer9 levels (Freyberg et al, 2010;Li et al, 2007;Xi et al, 2011). Synaptic GSK3β has been demonstrated to be important in synaptic plasticity regulation, and crosstalk between LTP and LTD (Peineau et al, 2007).…”