Abnormal Glu/mGluR2/3/PI3K pathway in the hippocampal neurovascular unit leads to diabetes-related depression

Jian Liu; Yuan-Shan Han; Lin Liu; Lin Tang; Hui Yang; Pan Meng; Hong-Qing Zhao; Yu-Hong Wang

doi:10.4103/1673-5374.296418

Abnormal Glu/mGluR_2/3/PI3K pathway in the hippocampal neurovascular unit leads to diabetes-related depression

Neural Regen Res. 2021 Apr;16(4):727-733. doi: 10.4103/1673-5374.296418.

Authors

Jian Liu¹, Yuan-Shan Han¹, Lin Liu¹, Lin Tang¹, Hui Yang¹, Pan Meng², Hong-Qing Zhao³, Yu-Hong Wang²

Affiliations

¹ The First Hospital, Hunan University of Chinese Medicine, Changsha, Hunan Province, China.
² Institute of Innovation and Applied Research; Key Laboratory of Chinese Material Medical Power and Innovation Drugs Established by Human Provincial Government and Ministry, Hunan University of Chinese Medicine; The Domestic First Class Construction Discipline of Chinese Medicine in Hunan University of Chinese Medicine, Changsha, Hunan Province, China.
³ Key Laboratory of Chinese Material Medical Power and Innovation Drugs Established by Human Provincial Government and Ministry; The Domestic First Class Construction Discipline of Chinese Medicine in Hunan University of Chinese Medicine, Changsha, Hunan Province, China.

Abstract

Our previous studies have shown that glutamate and hippocampal neuron apoptosis are key signals and direct factors associated with diabetes-related depression, and structural and functional damage to the hippocampal neurovascular unit has been associated with diabetes-related depression. However, the underlying mechanism remains unclear. We hypothesized that diabetes-related depression might be associated with the glutamate (Glu)/metabotropic glutamate receptor2/3 (mGluR_2/3)/phosphoinositide 3-kinase (PI3K) pathway, activated by glucocorticoid receptors in the hippocampal neurovascular unit. To test this hypothesis, rat hippocampal neurovascular unit models, containing hippocampal neurons, astrocytes, and brain microvascular endothelial cells, were treated with 150 mM glucose and 200 µM corticosterone, to induce diabetes-related depression. Our results showed that under conditions of diabetes complicated by depression, hippocampal neurovascular units were damaged, leading to decreased barrier function; elevated Glu levels; upregulated glucocorticoid receptor, vesicular glutamate transporter 3 (VGLUT-3), and metabotropic glutamate receptor 2/3 (mGluR_2/3) expression; downregulated excitatory amino acid transporter 1 (EAAT-1) expression; and alteration of the balance of key proteins associated with the extracellular signal-regulated kinase (ERK)/glial cell-derived neurotrophic factor (GDNF)/PI3K signaling pathway. Moreover, the viability of neurons was dramatically reduced in the model of diabetes-related depression, and neuronal apoptosis, and caspase-3 and caspase-9 expression levels, were increased. Our results suggest that the Glu/mGluR_2/3/PI3K pathway, induced by glucocorticoid receptor activation in the hippocampal neurovascular unit, may be associated with diabetes-related depression. This study was approved by the Laboratory Animal Ethics Committee of The First Hospital of Hunan University of Chinese Medicine, China (approval No. HN-ZYFY-2019-11-12) on November 12, 2019.

Keywords: diabetes-related depression; factor; hippocampus; in vitro; neurovascular unit; pathways; protein.