Role of astrocytes in the development and progression of major depressive disorder

Abstract

Major depressive disorder (MDD) is one of the most prevalent psychiatric illnesses worldwide which impairs the social functioning of the afflicted patients. Astrocytes play a role in the maintenance of the function of the central nervous system, both physiologically and pathologically. Increasing evidence suggests that the number, volume and function of astrocytes are altered in the depressed brain. The glial fibrillary acidic protein and S100β protein, which are closely associated with astrocytes, also show significant alterations in patients with MDD. Astrocyte-derived glial cell line-derived neurotrophic factor (GDNF) not only exerts neuroprotective effects in the central and peripheral nervous systems but also plays a role in depressive symptomatology and the pharmacological action of antidepressant treatments. Here, we summarize the physiological functions of astrocytes, alterations in the number and volume of astrocytes in MDD patients, changes in GDNF and S100β levels in MDD patients, and the association between MDD and GDNF-collectively highlighting the pivotal role of astrocytes in the development and progression of MDD.

Key Words: Astrocytes; Major depressive disorder; Glial fibrillary acidic protein; S100β protein; Glial cell line-derived neurotrophic factor; Physiological functions

Core Tip: Major depressive disorder is one of the most prevalent psychiatric illnesses worldwide which impairs the social functioning of the afflicted patients. Astrocytes play a role in the maintenance of the function of the central nervous system, both physiologically and pathologically. Increasing evidence suggests that the number, volume and function of astrocytes are altered in the depressed brain. The glial fibrillary acidic protein and S100β protein, which are closely associated with astrocytes, also show significant alterations in patients with major depressive disorder. Astrocyte-derived glial cell line-derived neurotrophic factor not only exerts neuroprotective effects in the central and peripheral nervous systems but also plays a role in depressive symptomatology and the pharmacological action of antidepressant treatments.

INTRODUCTION

Major depressive disorder (MDD) is a type of mood disorder characterized primarily by significant and persistent low mood, slowed thinking, reduced volitional activity, and physical discomfort. Its main clinical manifestations include depressed mood, lack of interest, and anhedonia, accompanied by symptoms such as decreased appetite, early awakening, and weight loss[1]. According to the 2019 epidemiological survey on mental disorders conducted by Huang et al[2], the prevalence of mood disorders was 4.06%, ranking second among all mental disorders after anxiety disorders. Among these, the prevalence of MDD was 3.6%. MDD ranks among the leading causes of disability worldwide. It not only harms patients’ health and reduces their quality of life but also places a significant burden on families and society, making it a serious social and medical issue[3]. However, the exact pathogenesis of MDD remains unclear. Diagnosis still relies on clinical symptoms, as no definitive biological markers are available. Furthermore, the efficacy of current antidepressant treatments remains limited.

Astrocytes are the predominant type of glial cells. Alongside neurons in the nervous system, there exists a vast population of glial cells that are widely distributed throughout both the central and peripheral nervous systems. Their number far exceeds those of neurons, constituting nearly 90% of all cells in the adult brain. Glial cells in the central nervous system (CNS) include astrocytes, oligodendrocytes, and microglia, with astrocytes constituting the majority and encompassing nearly all functions attributed to glial cells. In recent years, extensive research has been conducted on the morphology and functions of glial cells, with particularly significant advances in the study of astrocytes. For a long time in neurobiological research, astrocytes were considered secondary players, primarily responsible for providing structural support, nourishing neurons, and clearing excess ions and neurotransmitters from synaptic clefts. The term “glia”, derived from the Greek word for “glue”, reflects this historical view of their passive, supportive role. However, in 1997, Pfrieger and Barres[4] first reported that glial cells strongly enhance synaptic connectivity between neurons, marking a new era in understanding the glial function. Advancements in neuroscience research techniques and deeper investigations into astrocytes have demonstrated their crucial roles in nervous system development, synaptic transmission, neural tissue repair and regeneration, and neuroimmunity[5,6]. Astrocytic dysfunction has been implicated in several neurological diseases, including neuropsychiatric disorders such as MDD[7-11]. It contributes to the molecular pathogenesis of MDD[12] and can be rapidly and sustainably restored by ketamine treatment[13]. Therefore, astrocytes may serve as a therapeutic target for MDD[14-16]. In this review, we briefly summarized the physiological functions of astrocytes as well as the astrocyte-based pathophysiology of MDD (Figure 1). This review aimed to provide an overview of the proposed roles of astrocytes in normal brain function and the etiology and pharmacotherapy of MDD.

Figure 1 Multifunctional schematic diagram of astrocytes associated with major depressive disorder. RGC: Radial glial cell; mGluRs: Metabotropic glutamate receptors; GLT-1: Glutamate transporter 1; 5-HT: 5-hydroxytryptamine; ROS: Reactive oxygen species; cGAS-STING: Cyclic GMP-AMP synthase-stimulator of interferon genes; IL-6: Interleukin-6; IL-6R: Interleukin-6 receptor; TCA: Tricarboxylic acid cycle; BDNF: Brain-derived neurotrophic factor; GDNF: Glial cell line-derived neurotrophic factor; FGF2: Fibroblast growth factor 2; VEGF: Vascular endothelial growth factor; MDD: Major depressive disorder.

PHYSIOLOGICAL FUNCTIONS OF ASTROCYTES

Influence of astrocytes on synapses

For a long time, it was believed that synapse formation was solely related to neurons. However, recent studies have demonstrated that astrocytes also play a crucial role in this process[17,18]. For example, during normal development, most retinal ganglion cells extend their axons to the superior colliculus by embryonic day 16 in mice, but significant synapse formation begins only after the appearance of astrocytes nearly postnatal day 7[19]. This temporal correlation between astrocyte maturation and synapse formation suggests a potential connection between the two.

In the CNS, astrocytes guide synapse formation by releasing chemical factors, such as cholesterol, estrogens, and thrombospondins, thereby significantly increasing synapse numbers. Moreover, astrocytes themselves are essential components for synaptic function[20]. Research indicates that astrocytes play a vital role in supporting synaptic activity and promoting synapse maturation. When astrocytes are removed from the culture medium, preformed synapses on retinal ganglion cells fail to mature further, and their numbers decrease to one-fourth of the original count.

Astrocytes also regulate synaptic transmission. It was previously believed that synaptic connections could form solely between the presynaptic and postsynaptic membranes. However, recent studies have found that astrocytes are also a necessary component for synapse formation in the CNS. Astrocytes envelop synaptic terminals, enabling effective communication with synapses. Synaptic activation can trigger responses in astrocytes, which, by taking up glutamate, help modulate the duration of synaptic currents and prevent potential excitotoxic damage.

During high-frequency stimulation, glutamate activates glutamatergic receptors on astrocytes, leading to an increase in intracellular Ca²⁺ concentration. This, in turn, triggers the release of glutamate from astrocytes and negatively regulates neuronal glutamate release through metabotropic glutamate receptor dependent presynaptic inhibition. An additional effect of elevated Ca²⁺ levels in astrocytes is the propagation of Ca²⁺ waves to neighboring astrocytes through gap junctions, allowing signal modulation to spread to nearby synapses[21,22]. Accordingly, astrocytes have the potential to regulate synaptic transmission and synaptic plasticity, mechanisms that are also implicated in patients with MDD[23,24].

Regulation of energy demands in neurons and astrocytes

Astrocytes possess glucose transporter-rich end-feet that cover all capillary walls in the brain. Through these end-feet, glucose is supplied to meet the energy demands of both glial cells and neurons[25]. Within astrocytes, glucose undergoes glycolysis, providing energy for the conversion of intracellular glutamate to glutamine and for maintaining the Na⁺ gradient through Na⁺/K⁺-ATPase activity[26,27]. Astrocytes then release lactate into neurons, where it enters the tricarboxylic acid cycle and generates ATP through oxidative phosphorylation[28]. In astrocytes, glutamate-mediated synaptic activity is coupled with glucose uptake and utilization[29]. Functional magnetic resonance imaging and positron emission tomography studies allow the observation of signals collectively generated by glucose uptake, glycolysis, and oxidative phosphorylation[30,31]. ATP is an essential gliotransmitter involved in astrocytic modulation of depressive-like behavior[32]. Astrocytes, particularly the astrocyte mitochondrial melatonergic pathway, have been identified as crucial hubs for integrating the wide array of biological underpinnings of MDD[33,34].

Regulation of neurotransmitters

Cell culture and in vitro studies have revealed that astrocytes express all the receptors and ion channels found in neuron[35], including key transporters crucial for glutamate uptake at synapses and neuroprotection[36]. A vital function of astrocytes is the uptake of synaptic glutamate through their transporters. By absorbing glutamate, astrocytes terminate its postsynaptic action, reduce extracellular glutamate levels, and play a significant role in neuronal protection[37]. When astrocytes are co-cultured with neurons in vitro, they help protect neurons from death by maintaining low extracellular glutamate levels[38].

Furthermore, mice lacking the glutamate transporter-1 gene exhibit pronounced excitotoxic damage, further demonstrating the protective role of glutamate transport[36]. Antisense knockdown of glutamate transporters in rat brain astrocytes exacerbates neuronal injury[39]. Another glutamate-related function of astrocytes involves the enzyme glutamine synthetase (unique to astrocytes), which converts glutamate into glutamine. The released glutamine is taken up by neuronal terminals and reconverted into glutamate or gamma-aminobutyric acid, replenishing the neurotransmitter pool.

Astrocytes regulate extracellular neurotransmitter levels through specific transporters, modulating both synaptic availability and reuptake. In vitro studies have confirmed that astrocytes can absorb gamma-aminobutyric acid, 5-hydroxytryptamine (5-HT), dopamine (DA), norepinephrine, and histamine, as well as enzymes such as catechol-O-methyltransferase and monoamine oxidase, which further modulate extracellular neurotransmitters[40-48]. Moreover, antidepressants such as fluoxetine and paroxetine can block 5-HT uptake in cultured astrocytes, suggesting that both astrocytes and neurons may contribute to the therapeutic effects of antidepressants in MDD[49-51]. Reduced prefrontal glutamatergic function has been associated with decreased expression of astrocyte-related genes in treatment-resistant depression[52].

Neurotrophic functions

Astrocytes synthesize and release various neurotrophic factors and cytokines crucial for maintaining neuronal function, including nerve growth factor, brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), fibroblast growth factor 2, and neurotrophins 3, 4, and 5[53-55]. These factors support neuronal survival, growth, differentiation, synaptic plasticity, and efficacy[56]. Reactive astrocytes can also secrete molecules involved in glia-mediated angiogenesis, neuroregeneration, and neuronal precursor migration, such as endothelin, vascular endothelial growth factor, and angiopoietin[57].

Although the exact level of trophic support required for the survival of mature neurons remains unclear, deficiencies in these factors can increase susceptibility to cell death or damage[58]. Preclinical and postmortem human studies strongly suggest that reduced levels of neurotrophic factors, such as BDNF and fibroblast growth factor 2, and impaired neuroplasticity contribute significantly to the pathophysiology of MDD[59-63]. Antidepressant drugs and electroconvulsive therapy have been revealed to enhance BDNF expression in both glial cells and neurons and to stimulate the production of other neurotrophic and angiogenic factors, highlighting glial cells as a potential target for antidepressant treatment[64-66].

Estrogen contributes to the maintenance and restoration of normal brain function and promotes synaptic plasticity, serving as a neuroprotective factor in the CNS[67]. It exerts its neuroprotective effects either directly on neurons or indirectly through glial mediation. In vitro studies have identified estrogen receptors in astrocytes[68]. The absence of glial cells can impair estrogen-mediated neuroprotection, rendering neurons more vulnerable to neurotoxicity. Cell culture studies have demonstrated that estrogen upregulates the expression of glutamate transporters in astrocytes, thereby reducing extracellular glutamate levels and protecting neurons from glutamate-induced excitotoxicity[69]. In ovariectomized rats, estradiol has been revealed to upregulate mRNA and protein levels of glutamine synthetase in the hypothalamus and hippocampus, highlighting the role of astrocytes in hormone-regulated glutamatergic neurotransmission[70]. Consequently, the observed reduction in astrocyte numbers in postmortem brain tissue from patients with MDD may be linked to impaired estrogen-mediated neuroprotection.

Involvement in inflammatory processes and regulation of extracellular ion concentrations

Astrocytes are associated with neurodegenerative diseases, inflammatory processes, and regeneration[71,72]. Upon encountering injury, astrocytes become activated, leading to increases in cell number and size, as well as alterations in gene expression patterns, most notably, a marked upregulation of glial fibrillary acidic protein (GFAP). Activated astrocytes may play crucial roles in both inhibiting and promoting damage[73,74]. For example, astrocytes can form glial scars that prevent axonal regeneration; however, these scars may also help limit the spread of injury. Increased astrocyte proliferation does not necessarily indicate enhanced neurodegeneration but may instead reflect nonspecific repair processes that require glial activation. In response to injury, activated astrocytes also release neurotrophic factors that promote neuronal survival and repair.

Astrocytes maintain the neuronal microenvironment at an optimal level by regulating ion concentrations and metabolic substrates. Through gap junctions, they establish connections with numerous CNS cells, allowing the passage of small ions and molecules, such as K⁺, Ca²⁺, lactate, glucose, and amino acids. Additionally, astrocytes regulate intracellular pH, electrolyte balance, and extracellular space volume in the CNS through Na⁺/K⁺-ATPase activity on their cell membranes[75]. The rapid-acting antidepressant ketamine may exert excitatory effects on neurons by influencing the ability of astrocytes to regulate extracellular K⁺, thereby alleviating depressive symptoms[76]. One study identifies that the selective knockdown of interleukin-6 (IL-6) in microglia and IL-6 receptors in astrocytes effectively mitigates depression-like behaviors and reduces astrocyte atrophy. Thus, the microglial IL-6 appears to be a key factor contributing to astrocyte apoptosis and depressive symptoms[77].

Recent studies have indicated that astrocyte-mediated inflammation in MDD not only leads to elevated cytokine levels but also involves intracellular and intercellular signaling axes that can impact metabolic homeostasis. For instance, novel findings reveal that the cyclic GMP-AMP synthase-stimulator of interferon genes pathway, acting as a bridge between organelle stress and innate immune responses, links chronic stress signals from mitochondria and the endoplasmic reticulum to type I interferon responses. This finding suggests that chronic organelle stress may progressively transform reversible astrocytic responses into irreversible, inflammation-driven loss of ion regulatory capacity[78,79].

Collectively, these findings suggest that future research should move beyond simple enumeration of cytokine levels to explore how specific inflammatory signaling pathways disrupt astrocytic ion homeostasis and metabolic coupling functions in distinct brain regions and across genders. A research shift of this nature will facilitate a more thorough elucidation of the intrinsic link between neuroinflammation and neural circuit dysfunction in MDD.

Mitochondrial metabolism and signaling in astrocytes

A multitude of studies have demonstrated that mitochondrial metabolism and signaling pathways in astrocytes play a pivotal integrative role in the pathology of MDD, thereby linking metabolic, redox, inflammatory, and neurotransmitter-related dysfunctions[34]. Specifically, the inhibition of astrocyte-associated mitochondrial metabolic and signaling pathways results in impaired mitochondrial function, increased reactive oxygen species, and reactive oxygen species-dependent microRNA alterations, thereby promoting a pro-inflammatory phenotype in astrocytes[80]. Conversely, enhancing mitochondrial metabolism and signaling pathways in astrocytes has been shown to improve mitochondrial function and suppress inflammation. This provides a key mechanistic pathway for understanding MDD. This pathway translates intracellular metabolic and inflammatory dysregulation into neural circuit dysfunction and associated behavioral phenotypes[81].

SEX AND GENDER INFLUENCES ON ASTROCYTE FUNCTION

Gender has been identified as a critical factor that modulates the risk of depression and the associated neurobiological responses. The lifetime prevalence of MDD is significantly higher in women than in men, with this disparity emerging around adolescence. This discrepancy is presumably attributable to the synergistic effect of biological factors, including sex hormones, and psychosocial elements[82]. Astrocytes, in particular, have been observed to demonstrate gender disparities not only at rest but also in response to stress or hormonal stimulation.

Recent studies have revealed gender and brain region specific transcriptional and morphological characteristics of astrocytes[83], which may partially explain gender disparities in depression susceptibility. With regard to specific mechanisms, estrogen and other gonadal steroids have been demonstrated to directly regulate astrocytic inflammatory responses, glutamate metabolism, and neurotrophic factor expression. The cyclical or phasic fluctuations of these hormones have been shown to correlate with periods of heightened depression risk. This suggests the possibility that they may influence gender-specific manifestations of depression through interactions with astrocytes[84,85]. Consequently, when investigating astrocyte-related mechanisms in MDD, it is imperative to consider gender as a critical biological variable. The presentation of gender-stratified results is to be encouraged whenever possible, and the documentation or control of hormonal status is to be incorporated into experimental methodologies.

ALTERATIONS IN THE NUMBER AND VOLUME OF ASTROCYTES IN MDD

Several postmortem cell-counting studies on brain tissues of patients with MDD have revealed a significant reduction in the density and number of Nissl-stained astrocytes[86]. Moreover, compared with age-matched healthy controls, ultrastructural changes and alterations in the size of astrocyte nuclei have been observed in patients with MDD[87]. The decrease in astrocyte numbers has been primarily identified in specific frontal-limbic brain regions, such as the ventral anterior cingulate cortex (Brodmann area 24)[88], the dorsolateral prefrontal cortex (Brodmann area 9)[89-91], the pregenual anterior cingulate cortex[92], and the orbitofrontal cortex[90]. In contrast, some studies have reported an increased density of astrocytes in the hippocampal cornu ammonis region and the granular cell layer of the dentate gyrus in patients with MDD[93]. This increase in astrocyte density may be associated with a reduction in astrocytic processes rather than a proliferation of astrocytes[94]. Additionally, a significant decrease in astrocyte numbers has been found in the amygdala of patients with MDD and those with untreated bipolar disorder[95]. Suicidal behaviors in individuals with affective disorder may be related to astrocyte loss[96].

Beyond astrocyte density, the volume and morphology of astrocytes are also affected in patients with mood disorders[97]. Among six studies investigating astrocyte somatic volume in patients with MDD or bipolar disorder, three reported a significant enlargement of astrocyte cell bodies in the dorsolateral prefrontal cortex of both patient groups, as well as in the anterior cingulate cortex of patients with MDD, compared with non-psychiatric controls[98,99]. However, the other three studies found no changes in astrocyte somatic volume[100]. Furthermore, alterations in the roundness of astrocyte nuclei have been observed in the dorsolateral prefrontal cortex of patients with bipolar disorder[101]. The decrease in astrocyte density occurs alongside an increase in astrocyte nuclear volume, suggesting possible compensatory mechanisms. It can be hypothesized that reduced astrocyte density may indicate a loss of functionally normal astrocytes, while the remaining intact astrocytes may undergo hypertrophy to meet the metabolic demands of surrounding neurons, leading to changes in nuclear morphology and size. Notably, the increase in astrocyte nuclear volume may be specific to patients with MDD, as no such changes have been observed in patients with schizophrenia[102]. Moreover, studies on brain tissues of alcohol-dependent individuals, with or without MDD symptoms, have revealed a reduction in astrocyte nuclear volume.

Neuroimaging studies in humans have demonstrated selective hippocampal volume reduction in stress-related psychiatric disorders such as depression[103], a finding that has been replicated in chronic animal stress models[104]. However, the exact mechanism underlying hippocampal volume loss remains unclear. Massive neuronal loss due to repeated exposure to high cortisol levels is unlikely, as postmortem analyses of brain tissues from patients with MDD, steroid-treated individuals, and primates have revealed no significant cell loss or neuropathological changes[105,106]. Studies in chronic stress animal models suggest that hippocampal volume correlates with astrocyte number and cellular morphology. Stress-induced reductions in astrocyte number and size may contribute to hippocampal shrinkage. Notably, fluoxetine has been indicated to reverse these changes, helping maintain normal hippocampal volume in rats[107]. Moreover, one study found that electroacupuncture can prevent the reduction of astrocyte volume, thereby improving depressive-like behaviors in mice[108].

ALTERATIONS IN GFAP AND S100Β PROTEIN IN MDD

GFAP is an acidic protein with a molecular weight of 50-52 kDa and is a major structural component of astrocytes. Rich in glutamate and aspartate, GFAP exists in glial cells in two forms, intermediate filament protein and soluble protein, and functions as a cytoskeletal element in astrocytes. Its expression increases when astrocytes are stimulated or activated, making GFAP a specific marker for astrocytes and a recognized indicator of astrocyte activation[109]. Elevated GFAP levels in activated astrocytes may have neuroprotective effects. As a reliable marker for astrocyte activity, the intensity of GFAP immunohistochemical staining can reflect the degree of cellular activation. Studies have revealed reduced GFAP immunohistochemical staining in the hippocampus of patients with MDD and stress-induced animal models[10,110]. In the frontal cortex of patients with MDD, decreased gene expression has been observed for GFAP, a specific astrocytic protein, as well as for glutamate transporters in glial cells and glutamine synthetase[111]. Previous clinical studies have demonstrated increased GFAP serum levels in patients with MDD, with a trend toward higher levels correlating with increased severity of depression episodes according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria[112]. Serum GFAP may aid in the differential diagnosis of MDD and allow for objective quantification of depression severity. Furthermore, it may serve as a marker for monitoring astroglial pathology throughout the course of MDD[108]. In animal models, treatment with the classical antidepressant fluoxetine or electroacupuncture has been indicated to normalize astrocytic morphology in the prefrontal cortex and alleviate depressive-like behaviors[113].

A substantial body of evidence from human MDD studies supports the hypothesis that GFAP alterations measured in brain tissue primarily reflect changes in parenchymal astrocytes rather than peripheral glial cells. Initially, studies have demonstrated that GFAP immunoreactivity colocalizes with the typical morphology of cortical astrocytes at the protein and morphological levels. Its expression pattern correlates with the downregulation trend of astrocyte-specific markers (e.g., aquaporin-4, connexin 43), and cell density analysis confirms that GFAP-positive cells are highly correlated with astrocyte counts while showing no association with other glial cell types[114,115]. Secondly, at the molecular transcriptional level, studies employing single-nucleus RNA sequencing in postmortem prefrontal cortex tissue have demonstrated the capacity to discern cell clusters, including astrocytes. This finding indicates that alterations in gene expression profiles characteristic of MDD manifest exclusively in astrocytes and do not extend to peripheral glial transcription features[116,117]. In summary, high-resolution cellular analysis techniques, such as immunohistochemical localization and monocyte transcriptomics, suggest that GFAP alterations reported in MDD brain tissue primarily originate from central astrocytes. However, when utilizing GFAP in cerebrospinal fluid or serum as a biomarker, contamination from peripheral sources has been observed. Therefore, interpretation should incorporate cell-type-specific evidence and proceed with caution[118,119].

S100β is a 21 kDa acidic calcium-binding protein abundantly present in the CNS, where it performs various biological functions. Under physiological conditions, S100β is primarily produced by astrocytes and acts on neurons and their surrounding microenvironment. In contrast to other astrocytic proteins, excessively high levels of S100β can exert neurotoxic effects[120]. Elevated levels of S100β in cerebrospinal fluid and serum have been consistently correlated with MDD in unmedicated patients, serving as a potential state marker. Some studies have also revealed that S100β levels correlate with symptom severity and that their normalization may predict a successful treatment response[121-123]. Elevated serum S100β levels have been observed in patients with MDD and those with untreated bipolar disorder, whereas antidepressant treatment has been demonstrated to reduce these levels[124,125]. Blood and cerebrospinal fluid levels of S100β are consistently elevated in patients with MDD, and a significant positive correlation has been found between serum S100β levels and Hamilton Depression Rating Scale scores in patients with MDD[126,127]. Conversely, although S100β is highly expressed in astrocytes and correlates with disease status and treatment efficacy in MDD, interpreting it as a specific astrocyte-derived marker requires mechanistic support. This phenomenon is primarily attributable to the multifactorial and complex nature of its release. S100β can be released via exocytosis[128] or passively released during cellular injury or disruption of the blood-brain barrier[129]. Additionally, under certain conditions, its origin can also be traced to non-astrocytic sources[130]. In summary, in research and clinical practice, the interpretation of S100β or GFAP levels in bodily fluids, such as cerebrospinal fluid or serum, should integrate cell-type-specific detection techniques with assessments of blood-brain barrier integrity.

GDNF AND MDD

In 1993, Lin et al[131] isolated, purified, and successfully cloned glial cell line-derived GDNF from the rat B49 glial cell line. The human GDNF gene is located at 5p13.1-13.3 and shares 93% amino acid sequence homology with rat GDNF. GDNF is synthesized as a precursor and then processed into a mature 134-amino acid protein before secretion. It contains seven conserved cysteine residues and has a structural arrangement similar to that of the transforming growth factor-β (TGF-β) superfamily, classifying it as a member of this family. GDNF exerts its neurotrophic effects through two receptor subunits: GDNF family receptor alpha (GFR-α) and the receptor tyrosine kinase (Ret). GDNF first binds to GFR-α, forming a GDNF-GFR-α complex, which then recruits Ret to form a ternary complex. This interaction induces Ret dimerization and autophosphorylation of tyrosine residues, thereby initiating downstream signal transduction pathways[132].

GDNF promotes the survival of CNS neurons, including midbrain dopaminergic neurons, motor neurons, and norepinephrine neurons in the locus coeruleus. It also supports peripheral neurons, such as sympathetic and parasympathetic neurons, as well as sensory and enteric neurons. GDNF is the most potent neurotrophic factor identified for cholinergic motor neurons, enhancing their survival and acetylcholinesterase activity in cultured or developing neurons[133]. During neuronal development, GDNF acts synergistically with TGF-β2 and TGF-β3 to provide specific survival signals that guide DA neuron axon migration. In vitro studies, GDNF enhances the growth and differentiation of fetal midbrain DA neurons and increases astrocyte proliferation. Following brain injury, GDNF mRNA expression is altered, kainic acid- or pilocarpine-induced neuronal damage in rats leads to seizures and upregulates GDNF mRNA in the hippocampus, striatum, and cortex, suggesting a neuroprotective role in injury responses.

GDNF is one of the most potent factors for dopaminergic neurons and reveals therapeutic potential in Parkinson’s disease. It improves DA metabolism in the substantia nigra and striatum, repairs neurotoxin-damaged dopaminergic neurons, and enhances neuronal survival and synaptic density in Parkinson’s disease animal models, thereby reducing motor deficits[134].

GDNF knockout mice die shortly after birth, exhibiting deficits in neuronal and neural crest cell differentiation, loss of autonomic, trigeminal, and spinal motor neurons, complete absence of enteric neurons, and kidney malformations[135]. In embryonic kidneys, GDNF functions as a mesenchyme-derived signal that promotes ureteric bud branching. It also regulates spermatogonial differentiation, with its levels in the testes determining the fate of undifferentiated spermatogonia[136].

GDNF knockout mice exhibit abnormal hippocampal synaptic transmission[137]. Other studies have also demonstrated the significant role of GDNF in cognitive dysfunction and drug dependence[138,139]. Both GDNF and its receptors are highly expressed in the hippocampus and prefrontal cortex, brain regions critically involved in the pathogenesis and treatment of MDD[140]. In vitro studies using C6 glioma cell lines and cultured rat astrocytes have indicated that 5-HT, antidepressants, and mood stabilizers (such as lithium and valproate) significantly increase GDNF secretion[141-144]. While numerous biological factors and pharmacological agents can modulate GDNF expression, the intracellular regulatory pathways remain unclear[145]. Notably, research has revealed that blocking the extracellular signal-regulated protein kinase system can partially attenuate fluoxetine-induced upregulation of GDNF mRNA expression in astrocytes, highlighting the crucial role of extracellular signal-regulated protein kinase in cell growth and survival[146].

Animal studies have revealed that antidepressants do not significantly affect the mRNA expression of GDNF and its receptors, whereas mood stabilizers such as lithium can increase GDNF protein levels in the brains of depressed rat models[147]. In animal models of electroconvulsive therapy, electroconvulsive stimulation was found to reduce GDNF concentrations in the hippocampal and striatal regions of rats[148]. However, other studies reported that while electroconvulsive stimulation exhibited no significant effect on GDNF mRNA expression in the rat hippocampus, it markedly increased the mRNA expression of GDNF receptors.

Takebayashi et al[149] investigated serum GDNF levels in patients with partial or complete remission of MDD and bipolar disorder. They found that the serum GDNF levels in these patients were significantly lower than those in the normal control group. In contrast, Rosa et al[150] found that during manic or depressive episodes in patients with bipolar disorder, serum GDNF protein concentration increased. In two recent studies, Otsuki et al[151] reported that during depressive episodes in patients with MDD, GDNF mRNA expression in peripheral blood decreased, whereas, during remission, expression levels did not differ significantly from those of healthy controls. Michel et al[152] found that GDNF concentrations in the parietal cortex of patients with MDD were significantly higher than those in matched controls, whereas GDNF levels in the hippocampus were decreased. Liu et al[153] found that reduced plasma levels of GDNF may serve as a valuable diagnostic marker for first-episode MDD. Moreover, their preliminary finding suggests that baseline plasma GDNF levels could have prognostic value, higher levels may predict a better response to antidepressant treatment in patients with first-episode MDD.

It is noteworthy that GDNF expression demonstrates a high degree of pleiotropy and complexity. In conditions involving neuroinflammation or injury, both reactive astrocytes and microglia have been observed to induce GDNF production. Additionally, peripheral glial cells, such as Schwann cells, have been identified as sources under specific pathological conditions[154,155]. Furthermore, GDNF can be transported via extracellular vesicles[156], providing a mechanistic basis for intercellular communication and its detection in bodily fluids. Consequently, in the context of MDD research, the attribution of GDNF level changes to a particular cell type demands the integration of cell-resolution techniques with meticulous brain region and clinical stratification analyses[152].

CONCLUSION

Astrocytes perform complex functions in both developing and mature brains, including generating neuronal precursors, supporting neuronal metabolism, regulating neurotransmitter conversion and release, facilitating vascular remodeling, and controlling cerebral blood flow. Dysfunction or astrocytes in the number and morphology in emotion-related brain regions may contribute to MDD pathogenesis or progression.

Although no definitive neuropathological or neurodegenerative changes have been identified in the brains of patients with MDD, accumulating evidence suggests that astrocyte numbers are reduced in the frontal cortex of patients with MDD and those with bipolar disorder compared to non-psychiatric controls. Future research should aim to elucidate the factors that influence astrocyte proliferation and differentiation during brain development, depressive episodes, and disease progression, as well as the role of other glia-derived factors. Furthermore, it is crucial to ascertain whether alterations in glial cell lineage markers (such as GDNF, S100β, and GFAP) reflect astrocyte-specific dysfunction or broader glial and vascular reactivity. This is necessary for distinguishing depression-state-related astrocytic changes from stable characteristics. In addition, mounting evidence indicates that astrocytic reactivity exhibits gender and region-specific patterns, emphasizing the importance of stratified experimental designs. The integration of studies of metabolic, inflammatory, and neurotrophic pathways within this framework has the potential to identify astrocyte-targeted intervention strategies, thereby enhancing precision in depression treatment. Such studies may help determine whether therapies targeting glia-derived factors can alleviate depressive symptoms. Additionally, further investigation is needed to clarify whether changes in astrocyte physiology and number are state markers, present only during depressive episodes, or trait markers that persist even during remission.

ACKNOWLEDGEMENTS

We would like to express our gratitude to all the doctors and nurses of the Affective Disorders Research Team at the Affiliated Kangning Hospital of Ningbo University, who participated in this study. We also sincerely thank Jin Li, Wen-Xi Sun, and Peng Chen from Suzhou Guangji Hospital for their support.