Novel synergistic treatment for depression: involvement of GSK3β-regulated AMPA receptors in the prefrontal cortex of mice

Lei Guo; Shuzhuo Wang; Haihua Tian; Mengyuan Shang; Jia Xu; Chuang Wang

doi:10.1093/cercor/bhad299

Novel synergistic treatment for depression: involvement of GSK3β-regulated AMPA receptors in the prefrontal cortex of mice

Cereb Cortex. 2023 Oct 9;33(20):10504-10513. doi: 10.1093/cercor/bhad299.

Authors

Lei Guo^{1

2}, Shuzhuo Wang^{1

2}, Haihua Tian^{1

2

3}, Mengyuan Shang^{1

2}, Jia Xu^{1

2}, Chuang Wang^{1

2}

Affiliations

¹ Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo University, Ningbo, Zhejiang 315211, PR China.
² School of Basic Medical Science, Health Science Center, Ningbo University, Ningbo, Zhejiang 315211, PR China.
³ Department of Psychiatry, Ningbo Kangning Hospital, Ningbo, Zhejiang 315201, PR China.

PMID: 37566915
DOI: 10.1093/cercor/bhad299

Abstract

Previous evidence has suggested a vital role of glycogen synthase kinase 3β-mediated α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors trafficking in depression. Considering the antidepressant effect of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors activation in the prefrontal cortex, we hypothesized that glycogen synthase kinase 3β-induced alterations in α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors function in the prefrontal cortex participate in depression. Herein, we confirmed that the levels of phosphorylated glycogen synthase kinase 3β and GluA1, the latter being a subunit of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, were decreased in the prefrontal cortex of the chronic social defeat stress model mice presenting with depressive-like behaviors. We then found that a glycogen synthase kinase 3β (p.S9A) point mutation downregulated GluA1 and induced depressive-like behaviors in mice, whereas an agonist of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, PF-4778574 (2 mg/kg) did not reversed the molecular changes. On the other hand, the antidepressant effect of PF-4778574 was dose dependent, and the single administration of PF-4778574 at a lower dose (0.5 mg/kg) or of the glycogen synthase kinase 3β inhibitor SB216763 (5 and 10 mg/kg) did not evoke an antidepressant effect. In contrast, co-treatment with PF-4778574 (0.5 mg/kg) and SB216763 (10 mg/kg) led to antidepressant effects similar to those of PF-4778574 (2 mg/kg). Our results suggest that glycogen synthase kinase 3β-induced α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors dysfunction in the prefrontal cortex is one of the key mechanisms of depression, and the combination of a lower dose of PF-4778574 with SB216763 shows potential as a novel synergistic treatment for depression.

Keywords: GSK3β; major depressive disorder (MDD); α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPARs).

Abstract

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