In Vitro Models of Major Depressive Disorder

IN VITRO DEPRESSION MODELS

In vitro models of Major Depressive Disorder (MDD) serve as high-value translational tools in preclinical antidepressant discovery, bridging molecular target validation to distal biological efficacy within controlled cellular environments. These cellular platforms support high-throughput screening, simple operation, and relatively low assay cost, making them well suited for primary screening of large compound libraries. As a critical intermediate layer in the R&D pipeline, in vitro MDD models enable early-stage compound triage and mechanism-of-action deconvolution before in vivo studies. By prioritizing lead candidates with confirmed cellular efficacy and defined mechanisms, they can help reduce R&D spending, shorten development timelines, and improve the predictive reliability of subsequent in vivo efficacy evaluations.

MODEL SELECTION

Mechanism-driven in vitro model selection for depression drug discovery

Modeling Method	Corresponding Depression Mechanism	Commonly Used Cell Types	Key Molecular Pathways	Main Phenotypic Characteristics	Unique Value in Efficacy Evaluation
Glucocorticoid-induced (Corticosterone/Dexamethasone)	HPA axis hyperactivity, impaired neuroplasticity	SH-SY5Y, PC12, primary cortical/hippocampal neurons	GR → inhibit BDNF transcription → block mTORC1 pathway	Cell survival rate ↓, apoptosis ↑, BDNF ↓, p-mTOR ↓, synaptic proteins (PSD-95/GluA1) ↓	Most commonly used model, suitable for antidepressant screening and BDNF/mTOR pathway research
Glutamate-induced	Glutamate excitotoxicity	SH-SY5Y, PC12, primary cortical/hippocampal neurons	Overactivation of NMDA receptors → Ca²⁺ influx ↑ → ROS burst → mitochondrial damage	Cell survival rate ↓, calcium overload, ROS ↑, mitochondrial membrane potential ↓, antioxidant system (GSH) remodeling	Suitable for excitotoxicity research and rapid-acting antidepressant development
Lipopolysaccharide (LPS)-induced	Neuroinflammation hypothesis, abnormal activation of microglia	BV2 cells, microglia-neuron co-culture	TLR4/NF-κB pathway activation	Iba1 ↑ (microglial activation), IL-6/TNF-α/IL-1β ↑, indirectly leading to neuronal damage	Dedicated to neuroinflammatory mechanisms and inflammation-related depression research
Oxidative stress-induced (H₂O₂, 6-OHDA)	Mitochondrial dysfunction, oxidative damage	PC12, SH-SY5Y, primary cortical/hippocampal neurons	Lipid peroxidation chain reaction → DNA damage → mitochondrial membrane potential collapse	ROS ↑, MDA ↑, SOD ↓/GSH ↓, cell apoptosis rate ↑	Suitable for oxidative response research and mitochondrial protection agent evaluation

VALIDATED MODEL CASES

Validated in vitro model cases

Corticosterone (CORT)-Induced SH-SY5Y Cell Model

In the corticosterone-induced SH-SY5Y neuronal injury model, we offer CCK-8 cell viability assay and cellular ROS detection to evaluate neuroprotective effects of test compounds. Following co-incubation of SH-SY5Y cells with varying concentrations of corticosterone (CORT, 50–500 μM), cell viability decreases in a concentration-dependent manner, accompanied by a significant elevation in reactive oxygen species (ROS) levels. 200 μM CORT is selected as the optimal modeling concentration. Subsequent intervention with Fluoxetine (10–200 ng/mL) demonstrates a significant, concentration-dependent recovery in cell viability, indicating a clear neuroprotective effect.

CORT-induced SH-SY5Y cell viability and ROS detection

Figure 1. CCK-8 cell viability assay and cellular ROS detection in CORT-induced SH-SY5Y injury model

Glutamate (Glu)-Induced SH-SY5Y Cell Model

Co-incubation of SH-SY5Y cells with glutamate (Glu, 5–20 mM) results in a concentration-dependent reduction in cell viability alongside abnormal elevation of ROS levels. Using 20 mM Glu as the optimal modeling concentration, subsequent co-incubation with Fluoxetine (10–200 ng/mL) shows that the treatment effectively and dose-dependently reverses Glu-induced neurotoxicity and significantly enhances cell survival rate.

Glutamate-induced SH-SY5Y cell viability and ROS detection

Figure 2. CCK-8 cell viability assay and cellular ROS detection in Glu-induced SH-SY5Y injury model

6-OHDA-Induced SH-SY5Y Cell Model

Treatment of SH-SY5Y cells with 6-hydroxydopamine (6-OHDA, 80–250 μM) leads to a concentration-dependent decline in cell viability and a simultaneous increase in intracellular ROS levels. The 120 μM 6-OHDA concentration is selected to establish the injury model. Following treatment with Fluoxetine (10–200 ng/mL), cell viability in 6-OHDA-damaged cells is effectively restored in a dose-dependent manner.

6-OHDA-induced SH-SY5Y cell viability and ROS detection

Figure 3. CCK-8 cell viability assay and cellular ROS detection in 6-OHDA-induced SH-SY5Y injury model

Glutamate (Glu)-Induced Primary Cortical Neuron Model

In the glutamate-induced primary cortical neuron model, we provide CCK-8 cell viability assay and neuronal morphological analysis to assess compound protective effects against glutamate excitotoxicity. Co-incubation of primary cortical neurons with Glu (50–400 μM) reveals a significant, concentration-dependent decrease in neuronal survival rate. Furthermore, morphological analysis indicates that Glu treatment significantly reduces neurite number in primary cortical neurons, confirming structural damage to the neuronal network.

Glutamate-induced primary neuron viability and morphology analysis

Figure 4. CCK-8 viability assay and neuronal morphological analysis in Glu-induced primary cortical neuron model

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In Vitro Models of Major Depressive Disorder

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