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

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

doi:10.3389/fnins.2018.00756

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

Front Neurosci. 2018 Oct 23:12:756. doi: 10.3389/fnins.2018.00756. eCollection 2018.

Authors

Sung Woo Park^{1

2

3}, Rodrigo B Mansur^{4

5}, Yena Lee⁴, Jae-Hon Lee⁶, Mi Kyoung Seo¹, Ah Jeong Choi¹, Roger S McIntyre^{4

5

7}, Jung Goo Lee^{1

2

8}

Affiliations

¹ Paik Institute for Clinical Research, Inje University, Busan, South Korea.
² Department of Health Science and Technology, Graduate School, Inje University, Busan, South Korea.
³ Department of Convergence Biomedical Science, College of Medicine, Inje University, Busan, South Korea.
⁴ Mood Disorders Psychopharmacology Unit, University Health Network, University of Toronto, Toronto, ON, Canada.
⁵ Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
⁶ Department of Psychiatry, National Rehabilitation Center, Seoul, South Korea.
⁷ Department of Pharmacology, University of Toronto, Toronto, ON, Canada.
⁸ Department of Psychiatry, College of Medicine, Haeundae Paik Hospital, Inje University, Busan, South Korea.

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.

Keywords: glucagon-like peptide 1 receptor; liraglutide; mammalian target of rapamycin complex 1 signaling; neuroplasticity; toxic condition; α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor.