Establishment of a Depression Model Using Dexamethasone-treated Three-dimensional Cultured Rat Cortical Cells
Mi Kyoung Seo1,2,*, Sehoon Jeong3,*, Woo Seok Cheon4, Dong Yun Lee2, Sumin Lee5, Gyu-Hui Lee2, Deok-Gyeong Kang1, Dae-Hyun Seog1,6,7, Seong-Ho Kim2,8, Jung Goo Lee2,4, Sung Woo Park1,2
1Department of Convergence Biomedical Science, College of Medicine, Inje University, Busan, Korea
2Paik Institute for Clinical Research, Inje University, Busan, Korea
3Department of Artificial Intelligence and Data Science, Sejong University, Seoul, Korea
4Department of Psychiatry, Haeundae Paik Hospital, College of Medicine, Inje University, Busan, Korea
5Institute for Digital Antiaging and Healthcare, Inje University, Gimhae, Korea
6Department of Biochemistry, College of Medicine, Inje University, Busan, Korea
7Dementia and Neurodegenerative Disease Research Center, College of Medicine, Inje University, Busan, Korea
8Department of Internal Medicine, Haeundae Paik Hospital, College of Medicine, Inje University, Busan, Korea
Correspondence to: Sung Woo Park
Department of Convergence Biomedical Science, College of Medicine, Inje University, 75, Bokji-ro, Busanjin-gu, Busan 47392, Korea
E-mail: swpark@inje.ac.kr
ORCID: https://orcid.org/0000-0001-8601-9084
Jung Goo Lee
Department of Psychiatry, Haeundae Paik Hospital, College of Medicine, Inje University, 875, Haeun-daero, Haeundae-gu, Busan 48108, Korea
E-mail: iybihwc@inje.ac.kr
ORCID: https://orcid.org/0000-0003-3393-2667
*These authors contributed equally to this work.
Received: January 9, 2025; Revised: February 5, 2025; Accepted: February 6, 2025; Published online: March 10, 2025.
© The Korean College of Neuropsychopharmacology. All rights reserved.

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Abstract
Objective: In vitro models are useful for exploring the molecular mechanisms underlying impaired neuroplasticity in depression. In this study, we developed a three-dimensional spheroid model in which we investigated the effects of the synthetic glucocorticoid dexamethasone on key pathways involved in neuroplasticity, specifically BDNF, sirtuin 1, and mTORC1 signaling.
Methods: A micro-spheroid device was fabricated using photolithography and soft lithography, and cortical spheroids were generated from primary rat cortical cells. These spheroids, which contained neurons, astrocytes, microglia, and oligodendrocytes, were treated with various concentrations of dexamethasone.
Results: Dexamethasone treatment (100, 200, and 300 μM) resulted in a dose-dependent reduction in cell viability, BDNF mRNA expression, and neurite outgrowth. At 100 μM, dexamethasone reduced the expression of BDNF and sirtuin 1 and decreased the phosphorylation of ERK1/2. It also decreased the phosphorylation of mTORC1, 4E-BP1, and p70S6K, as well as synaptic proteins such as PSD-95 and GluA1.
Conclusion: Dexamethasone treatment inhibited pathways related to neuroplasticity. While dexamethasone-treated spheroids may serve as a basis for developing an in vitro model of depression, further validation is needed to confirm their broader applicability.
Keywords: Depression; Dexamethasone; Micro-spheroid device; Mechanistic target of rapamycin complex 1; Neuroplasticity; Spheroids.

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