Depression is a complex and multifactorial mental health disorder that affects millions worldwide, influencing mood, cognition, and overall well-being. Recent advances in neuroscience have highlighted the pivotal role of brain cells—particularly neurons, astrocytes, and microglia—in the development and persistence of depressive symptoms. Beyond chemical imbalances in neurotransmitters such as serotonin and dopamine, research now emphasizes cellular dysfunction, impaired neurogenesis, and inflammatory responses as central mechanisms contributing to depression.

Neurons are responsible for transmitting emotional and cognitive signals, and when their connectivity weakens—especially in the hippocampus and prefrontal cortex—symptoms like sadness, hopelessness, and memory decline often emerge. Astrocytes, traditionally viewed as support cells, regulate neurotransmitter levels and energy metabolism; their reduced activity has been linked to altered mood regulation. Meanwhile, microglia, the brain’s immune cells, can trigger neuroinflammation that disrupts neural communication and promotes depressive behavior.

Understanding how these brain cells interact under chronic stress and emotional trauma offers new perspectives for therapeutic interventions. Treatments targeting cellular repair, neuroplasticity enhancement, and inflammation control—such as antidepressant drugs, cognitive-behavioral therapy, and lifestyle changes—hold promise for restoring healthy brain function. This review underscores that depression is not solely a chemical disorder but a cellular one. Recognizing the interplay between brain cells and emotional states paves the way for more personalized, effective, and compassionate mental health care.

Depression is one of the most prevalent and disabling psychiatric disorders worldwide, affecting more than 300 million people and contributing significantly to global disease burden and suicide rates [1,2]. Traditionally, depression has been attributed to an imbalance of neurotransmitters such as serotonin, norepinephrine, and dopamine, forming the basis of the monoamine hypothesis [3]. However, growing evidence suggests that this explanation alone cannot fully account for the complex biological and psychological manifestations of the disorder [4,5]. Recent advances in neurobiology highlight the role of brain cells—neurons, astrocytes, and microglia—in shaping emotional regulation and vulnerability to depression [6,7].

Neurons are fundamental to signal transmission in the brain, and their impaired connectivity in regions such as the hippocampus and prefrontal cortex is strongly linked to mood disturbances, memory decline, and anhedonia [8,9]. Stress-induced neuronal atrophy and reduced synaptic plasticity have been consistently observed in both human and animal models of depression [10,11]. Furthermore, decreased neurogenesis and altered brain-derived neurotrophic factor (BDNF) signaling appear to exacerbate depressive symptoms [12,13].

Astrocytes, once considered merely supportive cells, are now recognized as active participants in neurotransmission, synaptic maintenance, and metabolic regulation [14,15]. Postmortem studies have demonstrated a marked reduction in astrocyte density in depressed patients, particularly within the anterior cingulate cortex and hippocampus [16,17]. Dysfunctional astrocytic glutamate clearance and impaired neurotrophic support contribute to excitotoxicity and neuronal dysfunction, further aggravating depressive pathology [18,19].

Microglia—the immune cells of the brain—play an equally crucial role. Chronic stress and systemic inflammation can trigger microglial activation, leading to the release of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α, which disrupt neurogenesis and synaptic plasticity [20,21]. Elevated microglial reactivity has been detected in the brains of individuals with major depressive disorder through positron emission tomography (PET) imaging and postmortem analysis [22,23]. Persistent neuroinflammation can impair neurotransmission, damage myelin integrity, and induce oxidative stress, all of which contribute to mood dysregulation [24–26].

Crosstalk between astrocytes and microglia further amplifies inflammatory cascades and glial dysfunction [27,28]. Recent studies have shown that the CX3CL1–CX3CR1 and NF-κB pathways are key mediators of this neuroinflammatory communication, linking cellular immune responses with depressive phenotypes [29,30]. Moreover, oxidative stress and mitochondrial abnormalities within glial cells alter brain metabolism and exacerbate depressive symptoms [31,32].

Understanding depression through a cellular lens shifts focus from neurotransmitters alone to broader neurobiological processes involving glial–neuronal interaction, immune signaling, and metabolic regulation [33,34]. Such insight is vital for the development of novel therapeutic strategies aimed at restoring cellular health, enhancing neuroplasticity, and reducing inflammation. This review discusses the critical interplay between neurons, astrocytes, and microglia in depression and highlights emerging therapeutic targets derived from these cellular mechanisms [35].