Liraglutide Activates mTORC1 Signaling and AMPA Receptors in Rat Hippocampal Neurons Under Toxic Conditions.

Sung Woo Park,Jae-Hon Lee,Roger S Mcintyre,Yena Lee,Mi Kyoung Seo,Jung Goo Lee,Rodrigo B Mansur,Ah Jeong Choi

doi:10.3389/fnins.2018.00756

Abstract

The aim of the present study was to determine whether treatment with liraglutide, a glucagon-like peptide 1 (GLP-1) receptor agonist, would alter mammalian target of rapamycin complex 1 (mTORC1) signaling and/or α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor activity under dexamethasone-induced toxic conditions. Western blot analyses were performed to assess changes in mTORC1-mediated proteins, brain-derived neurotrophic factor (BDNF), and various synaptic proteins (PSD-95, synapsin I, and GluA1) in rat hippocampal cultures under toxic conditions induced by dexamethasone, which causes hippocampal cell death. Hippocampal dendritic outgrowth and spine formation were measured using immunostaining procedures. Dexamethasone significantly decreased the phosphorylation levels of mTORC1 as well as its downstream proteins. However, treatment with liraglutide prevented these reductions and significantly increased BDNF expression. The increase in BDNF expression was completely blocked by rapamycin and 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX). Liraglutide also recovered dexamethasone-induced decreases in the total length of hippocampal dendrites and reductions in spine density in a concentration-dependent manner. However, the positive effects of liraglutide on neural plasticity were abolished by the blockade of mTORC1 signaling and AMPA receptors. Furthermore, liraglutide significantly increased the expression levels of PSD-95, synapsin I, and GluA1, whereas rapamycin and NBQX blocked these effects. The present study demonstrated that liraglutide activated mTORC1 signaling and AMPA receptor activity as well as increased dendritic outgrowth, spine density, and synaptic proteins under toxic conditions in rat primary hippocampal neurons. These findings suggest that GLP-1 receptor (GLP-1R) activation by liraglutide may affect neuroplasticity through mTORC1 and AMPA receptors.

Highlights

Depressive disorder is a very common psychiatric illness that typically has a chronic course (Andrade et al, 2003)
Specific kinase inhibitors were purchased from the following sources: PI3K inhibitor LY294002 from Cell Signaling Technology; MEK inhibitor PD98059 and mammalian target of rapamycin complex 1 (mTORC1) inhibitor rapamycin from Calbiochem (San Diego, CA, United States); and the amino-3-hydroxy-5methylisoxazole-4-propionic acid (AMPA) receptor inhibitor 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f] quinoxaline-7-sulfonamide (NBQX) from Tocris Bioscience (Ballwin, MO, United States)
The present study further examined whether the activations of mTORC1 signaling and AMPA receptors would contribute to the regulation of brain-derived neurotrophic factor (BDNF) expression induced by liraglutide following the administration of dexamethasone

Summary

Introduction

Depressive disorder is a very common psychiatric illness that typically has a chronic course (Andrade et al, 2003). The lifetime prevalence of depressive disorder is approximately 17% in the United States (Andrade et al, 2003; Kessler et al, 2003). The burden of illness associated with depressive disorder necessitates genuinely novel treatment approaches (Millan et al, 2015). More than 50 years after the monoamine hypothesis of depression has been proposed, several monoaminebased antidepressants have been developed. It is widely used as a pharmacological treatment for depression (Hillhouse and Porter, 2015). There is a need for innovative treatment strategies that utilize newly identified molecular mechanisms

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Methods

Results