Dpamine (DA) signaling has long been framed through a neuron-centric lens; yet, mounting evidence reveals that glial cells (astrocytes and microglia) serve as indispensable gatekeepers of dopaminergic tone, synaptic plasticity, and neuroimmune balance. Single-cell, spatial, and optical imaging studies have redefined DA circuits as multicellular ecosystems in which glial receptors, transporters, and gliotransmitters dynamically sculpt neuromodulation and behavior. Astrocytes fine-tune DA clearance, glutamate buffering, and metabolic coupling, while microglia integrate immune and stress cues recalibrate dopaminergic signaling across striatal and cortical circuits. Their bidirectional interactions, both glia-glia and glia-neuron, mediate resilience or vulnerability in contexts ranging from motivation and stress adaptation to Parkinson's disease (PD), depression, and post-viral fatigue syndromes. In this review, we synthesized emerging evidence that glial-DA crosstalk is a systems-level regulator of neuroinflammation and plasticity, bridging cellular metabolism, immune tone, and behavioral output. By integrating multi-omics, in vivo imaging, and computational models, we proposed a translational framework for targeting astrocytic and microglial states to restore dopaminergic homeostasis. Understanding and manipulating these non-neuronal interfaces may open the next frontier in precision neuropsychiatry and neurodegeneration therapeutics.
Citation: Moawiah M Naffaa. Glial-Dopamine crosstalk: Astrocytic and microglial gatekeepers of neuroinflammation, plasticity, and motivation[J]. AIMS Neuroscience, 2026, 13(1): 64-118. doi: 10.3934/Neuroscience.2026004
Dpamine (DA) signaling has long been framed through a neuron-centric lens; yet, mounting evidence reveals that glial cells (astrocytes and microglia) serve as indispensable gatekeepers of dopaminergic tone, synaptic plasticity, and neuroimmune balance. Single-cell, spatial, and optical imaging studies have redefined DA circuits as multicellular ecosystems in which glial receptors, transporters, and gliotransmitters dynamically sculpt neuromodulation and behavior. Astrocytes fine-tune DA clearance, glutamate buffering, and metabolic coupling, while microglia integrate immune and stress cues recalibrate dopaminergic signaling across striatal and cortical circuits. Their bidirectional interactions, both glia-glia and glia-neuron, mediate resilience or vulnerability in contexts ranging from motivation and stress adaptation to Parkinson's disease (PD), depression, and post-viral fatigue syndromes. In this review, we synthesized emerging evidence that glial-DA crosstalk is a systems-level regulator of neuroinflammation and plasticity, bridging cellular metabolism, immune tone, and behavioral output. By integrating multi-omics, in vivo imaging, and computational models, we proposed a translational framework for targeting astrocytic and microglial states to restore dopaminergic homeostasis. Understanding and manipulating these non-neuronal interfaces may open the next frontier in precision neuropsychiatry and neurodegeneration therapeutics.
| [1] |
Luo SX, Huang EJ (2016) Dopaminergic Neurons and Brain Reward Pathways: From Neurogenesis to Circuit Assembly. Am J Pathol 186: 478-488. https://doi.org/10.1016/j.ajpath.2015.09.023 
|
| [2] |
Morikawa H, Paladini CA (2011) Dynamic regulation of midbrain dopamine neuron activity: intrinsic, synaptic, and plasticity mechanisms. Neuroscience 198: 95-111. https://doi.org/10.1016/j.neuroscience.2011.08.023
|
| [3] |
Haber SN, Behrens TE (2014) The neural network underlying incentive-based learning: implications for interpreting circuit disruptions in psychiatric disorders. Neuron 83: 1019-1039. https://doi.org/10.1016/j.neuron.2014.08.031
|
| [4] |
Grace AA (2016) Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression. Nat Rev Neurosci 17: 524-532. https://doi.org/10.1038/nrn.2016.57
|
| [5] |
Booth HDE, Hirst WD, Wade-Martins R (2017) The Role of Astrocyte Dysfunction in Parkinson's Disease Pathogenesis. Trends Neurosci 40: 358-370. https://doi.org/10.1016/j.tins.2017.04.001
|
| [6] |
Li J, Serafin EK, Koorndyk N, et al. (2024) Astrocyte D1/D5 Dopamine Receptors Govern Non-Hebbian Long-Term Potentiation at Sensory Synapses onto Lamina I Spinoparabrachial Neurons. J Neurosci 44: e0170242024. https://doi.org/10.1523/JNEUROSCI.0170-24.2024
|
| [7] |
Guttenplan KA, Maxwell I, Santos E, et al. (2025) GPCR signaling gates astrocyte responsiveness to neurotransmitters and control of neuronal activity. Science 388: 763-768. https://doi.org/10.1126/science.adq5729
|
| [8] |
Santos DE, Silva Lima SA, Moreira LS, et al. (2025) New perspectives on heterogeneity in astrocyte reactivity in neuroinflammation. Brain Behav Immun Health 44: 100948. https://doi.org/10.1016/j.bbih.2025.100948
|
| [9] |
Favetta G, Bubacco L (2025) Beyond neurons: How does dopamine signaling impact astrocytic functions and pathophysiology?. Prog Neurobiol 251: 102798. https://doi.org/10.1016/j.pneurobio.2025.102798
|
| [10] |
Stedehouder J, Roberts BM, Raina S, et al. (2024) Rapid modulation of striatal cholinergic interneurons and dopamine release by satellite astrocytes. Nat Commun 15: 10017. https://doi.org/10.1038/s41467-024-54253-7
|
| [11] |
Frost JL, Schafer DP (2016) Microglia: Architects of the Developing Nervous System. Trends Cell Biol 26: 587-597. https://doi.org/10.1016/j.tcb.2016.02.006
|
| [12] |
She K, Yuan N, Huang M, et al. (2026) Emerging role of microglia in the developing dopaminergic system: Perturbation by early life stress. Neural Regen Res 21: 126-140. https://doi.org/10.4103/NRR.NRR-D-24-00742
|
| [13] |
Matt SM, Nolan R, Manikandan S, et al. (2025) Dopamine–driven increase in IL-1beta in myeloid cells is mediated by differential dopamine receptor expression and exacerbated by HIV. J Neuroinflammation 22: 91. https://doi.org/10.1186/s12974-025-03403-9
|
| [14] |
Gullotta GS, Costantino G, Sortino MA, et al. (2023) Microglia and the Blood-Brain Barrier: An External Player in Acute and Chronic Neuroinflammatory Conditions. Int J Mol Sci 24: 9144. https://doi.org/10.3390/ijms24119144
|
| [15] |
Hasel P, Aisenberg WH, Bennett FC, et al. (2023) Molecular and metabolic heterogeneity of astrocytes and microglia. Cell Metab 35: 555-570. https://doi.org/10.1016/j.cmet.2023.03.006
|
| [16] |
Franco R, Reyes-Resina I, Navarro G (2021) Dopamine in Health and Disease: Much More Than a Neurotransmitter. Biomedicines 9: 109. https://doi.org/10.3390/biomedicines9020109
|
| [17] | Belujon P, Grace AA (2015) Regulation of dopamine system responsivity and its adaptive and pathological response to stress. Proc Biol Sci 282: 20142516. https://doi.org/10.1098/rspb.2014.2516 |
| [18] |
Choi H, Lee EJ, Shin JS, et al. (2023) Spatiotemporal characterization of glial cell activation in an Alzheimer's disease model by spatially resolved transcriptomics. Exp Mol Med 55: 2564-2575. https://doi.org/10.1038/s12276-023-01123-9
|
| [19] |
Marchetti B, Giachino C, Tirolo C, et al. (2022) “Reframing” dopamine signaling at the intersection of glial networks in the aged Parkinsonian brain as innate Nrf2/Wnt driver: Therapeutical implications. Aging Cell 21: e13575. https://doi.org/10.1111/acel.13575
|
| [20] |
Martel JC, Gatti McArthur S (2020) Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia. Front Pharmacol 11: 1003. https://doi.org/10.3389/fphar.2020.01003
|
| [21] |
Sanz-Galvez R, Falardeau D, Kolta A, et al. (2024) The role of astrocytes from synaptic to non-synaptic plasticity. Front Cell Neurosci 18: 1477985. https://doi.org/10.3389/fncel.2024.1477985
|
| [22] |
Yu X, Nagai J, Marti-Solano M, et al. (2020) Context-Specific Striatal Astrocyte Molecular Responses Are Phenotypically Exploitable. Neuron 108: 1146-1162.e10. https://doi.org/10.1016/j.neuron.2020.09.021
|
| [23] |
Oda S, Funato H (2023) D1- and D2-type dopamine receptors are immunolocalized in pial and layer I astrocytes in the rat cerebral cortex. Front Neuroanat 17: 1111008. https://doi.org/10.3389/fnana.2023.1111008
|
| [24] |
Amato S, Averna M, Guidolin D, et al. (2023) Heteromerization of Dopamine D2 and Oxytocin Receptor in Adult Striatal Astrocytes. Int J Mol Sci 24: 4677. https://doi.org/10.3390/ijms24054677
|
| [25] |
Ma Z, Stork T, Bergles DE, et al. (2016) Neuromodulators signal through astrocytes to alter neural circuit activity and behaviour. Nature 539: 428-432. https://doi.org/10.1038/nature20145
|
| [26] |
Guidolin D, Tortorella C, Marcoli M, et al. (2023) Modulation of Neuron and Astrocyte Dopamine Receptors via Receptor-Receptor Interactions. Pharmaceuticals (Basel) 16: 1427. https://doi.org/10.3390/ph16101427
|
| [27] |
Pelassa S, Guidolin D, Venturini A, et al. (2019) A2A-D2 Heteromers on Striatal Astrocytes: Biochemical and Biophysical Evidence. Int J Mol Sci 20: 2457. https://doi.org/10.3390/ijms20102457
|
| [28] |
Bezerra TO, Roque AC (2024) Dopamine facilitates the response to glutamatergic inputs in astrocyte cell models. PLoS Comput Biol 20: e1012688. https://doi.org/10.1371/journal.pcbi.1012688
|
| [29] |
Khakh BS (2025) On astrocyte-neuron interactions: Broad insights from the striatum. Neuron 113: 3079-3107. https://doi.org/10.1016/j.neuron.2025.08.009
|
| [30] |
Malik AR, Willnow TE (2019) Excitatory Amino Acid Transporters in Physiology and Disorders of the Central Nervous System. Int J Mol Sci 20: 5671. https://doi.org/10.3390/ijms20225671
|
| [31] | Lazaridis IAG, Hirokane K, Choi W, et al. (2024) Striatal Astrocytes Influence Dopamine Dynamics and Behavioral State Transitions. biorxiv . https://doi.org/10.1101/2024.12.01.626240 |
| [32] |
Yin Y, Hu J, Wu H, et al. (2025) Astrocytic dopamine D1 receptor modulates glutamatergic transmission and synaptic plasticity in the prefrontal cortex through d-serine. Acta Pharm Sin B 15: 4692-4710. https://doi.org/10.1016/j.apsb.2025.07.034
|
| [33] |
Li J, Price TJ, Baccei ML (2022) D1/D5 Dopamine Receptors and mGluR5 Jointly Enable Non-Hebbian Long-Term Potentiation at Sensory Synapses onto Lamina I Spinoparabrachial Neurons. J Neurosci 42: 350-361. https://doi.org/10.1523/JNEUROSCI.1793-21.2021
|
| [34] |
Pittolo S, Yokoyama S, Willoughby DD, et al. (2022) Dopamine activates astrocytes in prefrontal cortex via alpha1-adrenergic receptors. Cell Rep 40: 111426. https://doi.org/10.1016/j.celrep.2022.111426
|
| [35] |
Amato S, Averna M, Farsetti E, et al. (2024) Control of Dopamine Signal in High-Order Receptor Complex on Striatal Astrocytes. Int J Mol Sci 25: 8610. https://doi.org/10.3390/ijms25168610
|
| [36] |
Purushotham SS, Buskila Y (2023) Astrocytic modulation of neuronal signalling. Front Netw Physiol 3: 1205544. https://doi.org/10.3389/fnetp.2023.1205544
|
| [37] |
Roberts BM, Lambert E, Livesey JA, et al. (2022) Dopamine Release in Nucleus Accumbens Is under Tonic Inhibition by Adenosine A(1) Receptors Regulated by Astrocytic ENT1 and Dysregulated by Ethanol. J Neurosci 42: 1738-1751. https://doi.org/10.1523/JNEUROSCI.1548-21.2021
|
| [38] |
Roberts BM, Doig NM, Brimblecombe KR, et al. (2020) GABA uptake transporters support dopamine release in dorsal striatum with maladaptive downregulation in a parkinsonism model. Nat Commun 11: 4958. https://doi.org/10.1038/s41467-020-18247-5
|
| [39] |
Lassus B, Naude J, Faure P, et al. (2018) Glutamatergic and dopaminergic modulation of cortico-striatal circuits probed by dynamic calcium imaging of networks reconstructed in microfluidic chips. Sci Rep 8: 17461. https://doi.org/10.1038/s41598-018-35802-9
|
| [40] |
Jennings A, Tyurikova O, Bard L, et al. (2017) Dopamine elevates and lowers astroglial Ca(2+) through distinct pathways depending on local synaptic circuitry. Glia 65: 447-459. https://doi.org/10.1002/glia.23103
|
| [41] |
Fischer T, Scheffler P, Lohr C (2020) Dopamine-induced calcium signaling in olfactory bulb astrocytes. Sci Rep 10: 631. https://doi.org/10.1038/s41598-020-57462-4
|
| [42] |
Petroccione MA, D'Brant LY, Affinnih N, et al. (2023) Neuronal glutamate transporters control reciprocal inhibition and gain modulation in D1 medium spiny neurons. Elife 12: e81830. https://doi.org/10.7554/eLife.81830.sa2
|
| [43] |
Martinez D, Rogers RC, Hermann GE, et al. (2020) Astrocytic glutamate transporters reduce the neuronal and physiological influence of metabotropic glutamate receptors in nucleus tractus solitarii. Am J Physiol Regul Integr Comp Physiol 318: R545-R564. https://doi.org/10.1152/ajpregu.00319.2019
|
| [44] |
Holly EN, Galanaugh J, Fuccillo MV (2024) Local regulation of striatal dopamine: A diversity of circuit mechanisms for a diversity of behavioral functions?. Curr Opin Neurobiol 85: 102839. https://doi.org/10.1016/j.conb.2024.102839
|
| [45] |
Cervetto C, Maura G, Guidolin D, et al. (2023) Striatal astrocytic A2A-D2 receptor-receptor interactions and their role in neuropsychiatric disorders. Neuropharmacology 237: 109636. https://doi.org/10.1016/j.neuropharm.2023.109636
|
| [46] |
Requie LM, Gomez-Gonzalo M, Speggiorin M, et al. (2022) Astrocytes mediate long-lasting synaptic regulation of ventral tegmental area dopamine neurons. Nat Neurosci 25: 1639-1650. https://doi.org/10.1038/s41593-022-01193-4
|
| [47] |
Dury LC, Yde Ohki CM, Lesch KP, et al. (2025) The role of astrocytes in attention-deficit hyperactivity disorder: An update. Psychiatry Res 350: 116558. https://doi.org/10.1016/j.psychres.2025.116558
|
| [48] |
Inagaki R, Kita S, Niwa N, et al. (2025) Aberrant extracellular dopamine clearance in the prefrontal cortex exhibits ADHD-like behavior in NCX3 heterozygous mice. FEBS J 292: 426-444. https://doi.org/10.1111/febs.17339
|
| [49] |
Zhuo Y, Luo B, Yi X, et al. (2024) Improved green and red GRAB sensors for monitoring dopaminergic activity in vivo. Nat Methods 21: 680-691. https://doi.org/10.1038/s41592-023-02100-w
|
| [50] |
MacDonald HJ, Kleppe R, Szigetvari PD, et al. (2024) The dopamine hypothesis for ADHD: An evaluation of evidence accumulated from human studies and animal models. Front Psychiatry 15: 1492126. https://doi.org/10.3389/fpsyt.2024.1492126
|
| [51] |
Sun F, Zhou J, Dai B, et al. (2020) Next-generation GRAB sensors for monitoring dopaminergic activity in vivo. Nat Methods 17: 1156-1166. https://doi.org/10.1038/s41592-020-00981-9
|
| [52] | Evans WR, Baskar SS, Costa A, et al. (2024) Functional activation of dorsal striatum astrocytes improves movement deficits in hemi-parkinsonian mice. bioRxiv . https://doi.org/10.1101/2024.04.02.587694 |
| [53] |
Karimi MA, Ghajari A, Khademi R, et al. (2024) Efficacy of preladenant in improving motor symptoms in Parkinson's disease: A systematic review and meta-analysis. IBRO Neurosci Rep 17: 207-219. https://doi.org/10.1016/j.ibneur.2024.07.005
|
| [54] |
Yu Y, Payne C, Marina N, et al. (2022) Remote and Selective Control of Astrocytes by Magnetomechanical Stimulation. Adv Sci (Weinh) 9: e2104194. https://doi.org/10.1002/advs.202104194
|
| [55] |
Corkrum M, Araque A (2021) Astrocyte-neuron signaling in the mesolimbic dopamine system: the hidden stars of dopamine signaling. Neuropsychopharmacology 46: 1864-1872. https://doi.org/10.1038/s41386-021-01090-7
|
| [56] |
Salinas AG, Lee JO, Augustin SM, et al. (2023) Distinct sub-second dopamine signaling in dorsolateral striatum measured by a genetically-encoded fluorescent sensor. Nat Commun 14: 5915. https://doi.org/10.1038/s41467-023-41581-3
|
| [57] |
Poewe W, Seppi K, Tanner CM, et al. (2017) Parkinson disease. Nat Rev Dis Primers 3: 17013. https://doi.org/10.1038/nrdp.2017.13
|
| [58] |
Kalia LV, Lang AE (2015) Parkinson's disease. Lancet 386: 896-912. https://doi.org/10.1016/S0140-6736(14)61393-3
|
| [59] |
Hou L, Bao X, Zang C, et al. (2018) Integrin CD11b mediates alpha-synuclein-induced activation of NADPH oxidase through a Rho-dependent pathway. Redox Biol 14: 600-608. https://doi.org/10.1016/j.redox.2017.11.010
|
| [60] |
Spillantini MG, Goedert M (2018) Neurodegeneration and the ordered assembly of alpha-synuclein. Cell Tissue Res 373: 137-148. https://doi.org/10.1007/s00441-017-2706-9
|
| [61] |
Qin J, Ma Z, Chen X, et al. (2023) Microglia activation in central nervous system disorders: A review of recent mechanistic investigations and development efforts. Front Neurol 14: 1103416. https://doi.org/10.3389/fneur.2023.1103416
|
| [62] |
Masuda T, Sankowski R, Staszewski O, et al. (2019) Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution. Nature 566: 388-392. https://doi.org/10.1038/s41586-019-0924-x
|
| [63] |
Ransohoff RM (2016) A polarizing question: do M1 and M2 microglia exist?. Nat Neurosci 19: 987-991. https://doi.org/10.1038/nn.4338
|
| [64] |
Rangaraju S, Dammer EB, Raza SA, et al. (2018) Quantitative proteomics of acutely-isolated mouse microglia identifies novel immune Alzheimer's disease-related proteins. Mol Neurodegener 13: 34. https://doi.org/10.1186/s13024-018-0266-4
|
| [65] |
Lloyd AF, Martinez-Muriana A, Davis E, et al. (2024) Deep proteomic analysis of microglia reveals fundamental biological differences between model systems. Cell Rep 43: 114908. https://doi.org/10.1016/j.celrep.2024.114908
|
| [66] |
Jayanti S, Dalla Verde C, Tiribelli C, et al. (2023) Inflammation, Dopaminergic Brain and Bilirubin. Int J Mol Sci 24: 11478. https://doi.org/10.3390/ijms241411478
|
| [67] |
Wong TS, Li G, Li S, et al. (2023) G protein-coupled receptors in neurodegenerative diseases and psychiatric disorders. Signal Transduct Target Ther 8: 177. https://doi.org/10.1038/s41392-023-01427-2
|
| [68] |
Han Q, Li W, Chen P, et al. (2024) Microglial NLRP3 inflammasome-mediated neuroinflammation and therapeutic strategies in depression. Neural Regen Res 19: 1890-1898. https://doi.org/10.4103/1673-5374.390964
|
| [69] |
Hanslik KL, Ulland TK (2020) The Role of Microglia and the Nlrp3 Inflammasome in Alzheimer's Disease. Front Neurol 11: 570711. https://doi.org/10.3389/fneur.2020.570711
|
| [70] |
Wang T, Nowrangi D, Yu L, et al. (2018) Activation of dopamine D1 receptor decreased NLRP3-mediated inflammation in intracerebral hemorrhage mice. J Neuroinflammation 15: 2. https://doi.org/10.1186/s12974-017-1039-7
|
| [71] |
Pike AF, Longhena F, Faustini G, et al. (2022) Dopamine signaling modulates microglial NLRP3 inflammasome activation: implications for Parkinson's disease. J Neuroinflammation 19: 50. https://doi.org/10.1186/s12974-022-02410-4
|
| [72] |
de Pablos RM, Herrera AJ, Espinosa-Oliva AM, et al. (2014) Chronic stress enhances microglia activation and exacerbates death of nigral dopaminergic neurons under conditions of inflammation. J Neuroinflammation 11: 34. https://doi.org/10.1186/1742-2094-11-34
|
| [73] |
Wendimu MY, Hooks SB (2022) Microglia Phenotypes in Aging and Neurodegenerative Diseases. Cells 11: 2091. https://doi.org/10.3390/cells11132091
|
| [74] |
Lind-Holm Mogensen F, Seibler P, Grunewald A, et al. (2025) Microglial dynamics and neuroinflammation in prodromal and early Parkinson's disease. J Neuroinflammation 22: 136. https://doi.org/10.1186/s12974-025-03462-y
|
| [75] |
Theis H, Pavese N, Rektorova I, et al. (2024) Imaging Biomarkers in Prodromal and Earliest Phases of Parkinson's Disease. J Parkinsons Dis 14: S353-S365. https://doi.org/10.3233/JPD-230385
|
| [76] |
Lee SH, Bae EJ, Park SJ, et al. (2025) Microglia-driven inflammation induces progressive tauopathies and synucleinopathies. Exp Mol Med 57: 1017-1031. https://doi.org/10.1038/s12276-025-01450-z
|
| [77] |
Deyell JS, Sriparna M, Ying M, et al. (2023) The Interplay between alpha-Synuclein and Microglia in alpha-Synucleinopathies. Int J Mol Sci 24: 2477. https://doi.org/10.3390/ijms24032477
|
| [78] |
Perry VH, Holmes C (2014) Microglial priming in neurodegenerative disease. Nat Rev Neurol 10: 217-224. https://doi.org/10.1038/nrneurol.2014.38
|
| [79] |
Tansey MG, Goldberg MS (2010) Neuroinflammation in Parkinson's disease: its role in neuronal death and implications for therapeutic intervention. Neurobiol Dis 37: 510-518. https://doi.org/10.1016/j.nbd.2009.11.004
|
| [80] |
Badanjak K, Fixemer S, Smajic S, et al. (2021) The Contribution of Microglia to Neuroinflammation in Parkinson's Disease. Int J Mol Sci 22: 4676. https://doi.org/10.3390/ijms22094676
|
| [81] |
Miao Y, Meng H (2024) The involvement of alpha-synucleinopathy in the disruption of microglial homeostasis contributes to the pathogenesis of Parkinson's disease. Cell Commun Signal 22: 31. https://doi.org/10.1186/s12964-023-01402-y
|
| [82] |
Li Y, Xia Y, Yin S, et al. (2021) Targeting Microglial alpha-Synuclein/TLRs/NF-kappaB/NLRP3 Inflammasome Axis in Parkinson's Disease. Front Immunol 12: 719807. https://doi.org/10.3389/fimmu.2021.719807
|
| [83] |
Gerhard A (2016) TSPO imaging in parkinsonian disorders. Clin Transl Imaging 4: 183-190. https://doi.org/10.1007/s40336-016-0171-1
|
| [84] |
Lavisse S, Goutal S, Wimberley C, et al. (2021) Increased microglial activation in patients with Parkinson disease using [(18)F]-DPA714 TSPO PET imaging. Parkinsonism Relat Disord 82: 29-36. https://doi.org/10.1016/j.parkreldis.2020.11.011
|
| [85] | Brooks NAH, Riar I, Klegeris A (2026) Mitochondrial damage-associated molecular patterns: Neuroimmunomodulators in central nervous system pathophysiology. Neural Regen Res 21: 1322-1338. https://doi.org/10.4103/NRR.NRR-D-24-01459 |
| [86] |
Deus CM, Tavares H, Beatriz M, et al. (2022) Mitochondrial Damage-Associated Molecular Patterns Content in Extracellular Vesicles Promotes Early Inflammation in Neurodegenerative Disorders. Cells 11: 2364. https://doi.org/10.3390/cells11152364
|
| [87] |
Zhu XX, Wang PJ, Chao S, et al. (2025) Transcriptomic profiling identifies ferroptosis and NF-kappaB signaling involved in alpha-dimorphecolic acid regulation of microglial inflammation. J Transl Med 23: 260. https://doi.org/10.1186/s12967-025-06296-7
|
| [88] |
Guan L, Lin L, Ma C, et al. (2025) Decoding crosstalk between neurotransmitters and alpha-synuclein in Parkinson's disease: pathogenesis and therapeutic implications. Ther Adv Neurol Disord 18: 17562864251339895. https://doi.org/10.1177/17562864251339895
|
| [89] |
Kang S, Noh Y, Oh SJ, et al. (2023) Neuroprotective Effects of Aldehyde-Reducing Composition in an LPS-Induced Neuroinflammation Model of Parkinson's Disease. Molecules 28: 7988. https://doi.org/10.3390/molecules28247988
|
| [90] |
Bailey HM, Cookson MR (2024) How Parkinson's Disease-Linked LRRK2 Mutations Affect Different CNS Cell Types. J Parkinsons Dis 14: 1331-1352. https://doi.org/10.3233/JPD-230432
|
| [91] |
Yoshioka Y, Sugino Y, Yamamuro A, et al. (2022) Dopamine inhibits the expression of proinflammatory cytokines of microglial cells through the formation of dopamine quinone in the mouse striatum. J Pharmacol Sci 148: 41-50. https://doi.org/10.1016/j.jphs.2021.10.004
|
| [92] |
Stokholm MG, Iranzo A, Ostergaard K, et al. (2017) Assessment of neuroinflammation in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a case-control study. Lancet Neurol 16: 789-796. https://doi.org/10.1016/S1474-4422(17)30173-4
|
| [93] |
Burke WJ, Li SW, Williams EA, et al. (2003) 3,4-Dihydroxyphenylacetaldehyde is the toxic dopamine metabolite in vivo: implications for Parkinson's disease pathogenesis. Brain Res 989: 205-213. https://doi.org/10.1016/S0006-8993(03)03354-7
|
| [94] |
Schafer DP, Lehrman EK, Stevens B (2013) The “quad-partite” synapse: microglia-synapse interactions in the developing and mature CNS. Glia 61: 24-36. https://doi.org/10.1002/glia.22389
|
| [95] |
Huo A, Wang J, Li Q, et al. (2024) Molecular mechanisms underlying microglial sensing and phagocytosis in synaptic pruning. Neural Regen Res 19: 1284-1290. https://doi.org/10.4103/1673-5374.385854
|
| [96] |
Soteros BM, Sia GM (2022) Complement and microglia dependent synapse elimination in brain development. WIREs Mech Dis 14: e1545. https://doi.org/10.1002/wsbm.1545
|
| [97] |
Loh JS, Mak WQ, Tan LKS, et al. (2024) Microbiota-gut-brain axis and its therapeutic applications in neurodegenerative diseases. Signal Transduct Target Ther 9: 37. https://doi.org/10.1038/s41392-024-01743-1
|
| [98] |
Juarez Olguin H, Calderon Guzman D, Hernandez Garcia E, et al. (2016) The Role of Dopamine and Its Dysfunction as a Consequence of Oxidative Stress. Oxid Med Cell Longev 2016: 9730467. https://doi.org/10.1155/2016/9730467
|
| [99] |
Cai Y, Liu J, Wang B, et al. (2022) Microglia in the Neuroinflammatory Pathogenesis of Alzheimer's Disease and Related Therapeutic Targets. Front Immunol 13: 856376. https://doi.org/10.3389/fimmu.2022.856376
|
| [100] |
Gao C, Jiang J, Tan Y, et al. (2023) Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets. Signal Transduct Target Ther 8: 359. https://doi.org/10.1038/s41392-023-01588-0
|
| [101] |
Vainchtein ID, Chin G, Cho FS, et al. (2018) Astrocyte-derived interleukin-33 promotes microglial synapse engulfment and neural circuit development. Science 359: 1269-1273. https://doi.org/10.1126/science.aal3589
|
| [102] |
Sun M, You H, Hu X, et al. (2023) Microglia-Astrocyte Interaction in Neural Development and Neural Pathogenesis. Cells 12: 1942. https://doi.org/10.3390/cells12151942
|
| [103] |
Spreng AS, Brull M, Leisner H, et al. (2022) Distinct and Dynamic Transcriptome Adaptations of iPSC-Generated Astrocytes after Cytokine Stimulation. Cells 11: 2644. https://doi.org/10.3390/cells11172644
|
| [104] |
Jiwaji Z, Tiwari SS, Aviles-Reyes RX, et al. (2022) Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Ass pathology. Nat Commun 13: 135. https://doi.org/10.1038/s41467-021-27702-w
|
| [105] |
Naffaa MM (2025) Mechanisms of astrocytic and microglial purinergic signaling in homeostatic regulation and implications for neurological disease. Explor Neurosci 4: 100676. https://doi.org/10.37349/en.2025.100676
|
| [106] |
Lindberg D, Shan D, Ayers-Ringler J, et al. (2015) Purinergic signaling and energy homeostasis in psychiatric disorders. Curr Mol Med 15: 275-295. https://doi.org/10.2174/1566524015666150330163724
|
| [107] |
Carracedo S, Launay A, Dechelle-Marquet PA, et al. (2024) Purinergic-associated immune responses in neurodegenerative diseases. Prog Neurobiol 243: 102693. https://doi.org/10.1016/j.pneurobio.2024.102693
|
| [108] |
Pawelec P, Ziemka-Nalecz M, Sypecka J, et al. (2020) The Impact of the CX3CL1/CX3CR1 Axis in Neurological Disorders. Cells 9: 2277. https://doi.org/10.3390/cells9102277
|
| [109] |
Chu Y, Harms AS, Boehringer A, et al. (2025) Decreased neuronal and increased endothelial fractalkine expression are associated with neuroinflammation in Parkinson's disease and related disorders. Front Cell Neurosci 19: 1557645. https://doi.org/10.3389/fncel.2025.1557645
|
| [110] |
Prada I, Gabrielli M, Turola E, et al. (2018) Glia-to-neuron transfer of miRNAs via extracellular vesicles: a new mechanism underlying inflammation-induced synaptic alterations. Acta Neuropathol 135: 529-550. https://doi.org/10.1007/s00401-017-1803-x
|
| [111] |
Pistono C, Bister N, Stanova I, et al. (2020) Glia-Derived Extracellular Vesicles: Role in Central Nervous System Communication in Health and Disease. Front Cell Dev Biol 8: 623771. https://doi.org/10.3389/fcell.2020.623771
|
| [112] |
Marchetti B, Leggio L, L'Episcopo F, et al. (2020) Glia-Derived Extracellular Vesicles in Parkinson's Disease. J Clin Med 9: 1941. https://doi.org/10.3390/jcm9061941
|
| [113] |
Nagai J, Yu X, Papouin T, et al. (2021) Behaviorally consequential astrocytic regulation of neural circuits. Neuron 109: 576-596. https://doi.org/10.1016/j.neuron.2020.12.008
|
| [114] |
Agarwal D, Sandor C, Volpato V, et al. (2020) A single-cell atlas of the human substantia nigra reveals cell-specific pathways associated with neurological disorders. Nat Commun 11: 4183. https://doi.org/10.1038/s41467-020-17876-0
|
| [115] |
Fornari Laurindo L, Aparecido Dias J, Cressoni Araujo A, et al. (2023) Immunological dimensions of neuroinflammation and microglial activation: exploring innovative immunomodulatory approaches to mitigate neuroinflammatory progression. Front Immunol 14: 1305933. https://doi.org/10.3389/fimmu.2023.1305933
|
| [116] |
Ma M, Paryani F, Jakubiak K, et al. (2025) The spatial landscape of glial pathology and T cell response in Parkinson's disease substantia nigra. Nat Commun 16: 7146. https://doi.org/10.1038/s41467-025-62478-3
|
| [117] |
Gaertner Z, Oram C, Schneeweis A, et al. (2025) Molecular and spatial transcriptomic classification of midbrain dopamine neurons and their alterations in a LRRK2(G2019S) model of Parkinson's disease. Elife 13: RP101035. https://doi.org/10.7554/eLife.101035.3
|
| [118] |
Rademacher K, Doric Z, Haddad D, et al. (2025) Chronic hyperactivation of midbrain dopamine neurons causes preferential dopamine neuron degeneration. Elife 13: RP98775. https://doi.org/10.7554/eLife.98775.3
|
| [119] |
Gao MY, Wang JQ, He J, et al. (2023) Single-Cell RNA-Sequencing in Astrocyte Development, Heterogeneity, and Disease. Cell Mol Neurobiol 43: 3449-3464. https://doi.org/10.1007/s10571-023-01397-7
|
| [120] |
Khan ZU, Koulen P, Rubinstein M, et al. (2001) An astroglia-linked dopamine D2-receptor action in prefrontal cortex. Proc Natl Acad Sci U S A 98: 1964-1969. https://doi.org/10.1073/pnas.98.4.1964
|
| [121] |
Rahimian R, Belliveau C, Chen R, et al. (2022) Microglial Inflammatory-Metabolic Pathways and Their Potential Therapeutic Implication in Major Depressive Disorder. Front Psychiatry 13: 871997. https://doi.org/10.3389/fpsyt.2022.871997
|
| [122] |
Kopec AM, Smith CJ, Ayre NR, et al. (2018) Microglial dopamine receptor elimination defines sex-specific nucleus accumbens development and social behavior in adolescent rats. Nat Commun 9: 3769. https://doi.org/10.1038/s41467-018-06118-z
|
| [123] |
Furuyashiki T, Kitaoka S (2019) Neural mechanisms underlying adaptive and maladaptive consequences of stress: Roles of dopaminergic and inflammatory responses. Psychiatry Clin Neurosci 73: 669-675. https://doi.org/10.1111/pcn.12901
|
| [124] |
Jimenez-Gonzalez A, Gomez-Acevedo C, Ochoa-Aguilar A, et al. (2022) The Role of Glia in Addiction: Dopamine as a Modulator of Glial Responses in Addiction. Cell Mol Neurobiol 42: 2109-2120. https://doi.org/10.1007/s10571-021-01105-3
|
| [125] |
Lee HG, Wheeler MA, Quintana FJ (2022) Function and therapeutic value of astrocytes in neurological diseases. Nat Rev Drug Discov 21: 339-358. https://doi.org/10.1038/s41573-022-00390-x
|
| [126] |
Mastroeni D, Grover A, Leonard B, et al. (2009) Microglial responses to dopamine in a cell culture model of Parkinson's disease. Neurobiol Aging 30: 1805-1817. https://doi.org/10.1016/j.neurobiolaging.2008.01.001
|
| [127] |
Mao S, Qiao R, Wang Q, et al. (2025) Activity and Heterogeneity of Astrocytes in Neurological Diseases: Molecular Mechanisms and Therapeutic Targets. MedComm (2020) 6: e70329. https://doi.org/10.1002/mco2.70329
|
| [128] | Yoo S LK, Seo J, Choi H, et al. (2024) Single-nucleus and spatial transcriptomic analysis identified molecular features of neuronal heterogeneity and distinct glial responses in Parkinson's disease. biorxiv . https://doi.org/10.1101/2024.07.28.605055 |
| [129] | Hu N, Chen L, Hu G, et al. (2025) Advancements in extracellular vesicle therapy for neurodegenerative diseases. Explor Neuroprotective Ther 5: 10.37349/ent.2025.1004104. https://doi.org/10.37349/ent.2025.1004104 |
| [130] |
Felger JC, Li Z, Haroon E, et al. (2016) Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression. Mol Psychiatry 21: 1358-1365. https://doi.org/10.1038/mp.2015.168
|
| [131] |
Felger JC, Miller AH (2012) Cytokine effects on the basal ganglia and dopamine function: the subcortical source of inflammatory malaise. Front Neuroendocrinol 33: 315-327. https://doi.org/10.1016/j.yfrne.2012.09.003
|
| [132] |
Sugama S, Takenouchi T, Hashimoto M, et al. (2019) Stress-induced microglial activation occurs through beta-adrenergic receptor: noradrenaline as a key neurotransmitter in microglial activation. J Neuroinflammation 16: 266. https://doi.org/10.1186/s12974-019-1632-z
|
| [133] |
Tujula I, Hyvarinen T, Lotila J, et al. (2025) Modeling neuroinflammatory interactions between microglia and astrocytes in a human iPSC-based coculture platform. Cell Commun Signal 23: 298. https://doi.org/10.1186/s12964-025-02304-x
|
| [134] | Iring A TA, Baranyi M, Otrokocsi L, et al. (2021) Central inhibition of P2Y12R differentially regulates survival and neuronal loss in MPTP-induced Parkinsonism in mice. biorxiv . |
| [135] |
Murphy-Royal C, Ching S, Papouin T (2023) A conceptual framework for astrocyte function. Nat Neurosci 26: 1848-1856. https://doi.org/10.1038/s41593-023-01448-8
|
| [136] |
Stowell R, Wang KH (2025) Dopaminergic signaling regulates microglial surveillance and adolescent plasticity in the mouse frontal cortex. Nat Commun 16: 7974. https://doi.org/10.1038/s41467-025-63314-4
|
| [137] |
Alcaro A, Huber R, Panksepp J (2007) Behavioral functions of the mesolimbic dopaminergic system: an affective neuroethological perspective. Brain Res Rev 56: 283-321. https://doi.org/10.1016/j.brainresrev.2007.07.014
|
| [138] |
Baik JH (2020) Stress and the dopaminergic reward system. Exp Mol Med 52: 1879-1890. https://doi.org/10.1038/s12276-020-00532-4
|
| [139] |
Ortinski PI, Reissner KJ, Turner J, et al. (2022) Control of complex behavior by astrocytes and microglia. Neurosci Biobehav Rev 137: 104651. https://doi.org/10.1016/j.neubiorev.2022.104651
|
| [140] |
Zhou ZC, Gordon-Fennell A, Piantadosi SC, et al. (2023) Deep-brain optical recording of neural dynamics during behavior. Neuron 111: 3716-3738. https://doi.org/10.1016/j.neuron.2023.09.006
|
| [141] |
Serra I, Martin-Monteagudo C, Sanchez Romero J, et al. (2025) Astrocyte ensembles manipulated with AstroLight tune cue-motivated behavior. Nat Neurosci 28: 616-626. https://doi.org/10.1038/s41593-025-01870-0
|
| [142] |
Kang S, Hong SI, Kang S, et al. (2023) Astrocyte activities in the external globus pallidus regulate action-selection strategies in reward-seeking behaviors. Sci Adv 9: eadh9239. https://doi.org/10.1126/sciadv.adh9239
|
| [143] |
Yang MA, Kang S, Hong SI, et al. (2025) Astrocytes in the External Globus Pallidus Selectively Represent Routine Formation During Repeated Reward-Seeking in Mice. eNeuro 12: ENEURO.0552–24.2025. https://doi.org/10.1523/ENEURO.0552-24.2025
|
| [144] |
Zhang C, Dulinskas R, Ineichen C, et al. (2024) Chronic stress deficits in reward behaviour co-occur with low nucleus accumbens dopamine activity during reward anticipation specifically. Commun Biol 7: 966. https://doi.org/10.1038/s42003-024-06658-9
|
| [145] |
Park K, Lee SJ (2020) Deciphering the star codings: astrocyte manipulation alters mouse behavior. Exp Mol Med 52: 1028-1038. https://doi.org/10.1038/s12276-020-0468-z
|
| [146] |
Nowak DB, Taborda-Bejarano JP, Chaure FJ, et al. (2025) Understanding Microglia in Mesocorticolimbic Circuits: Implications for the Study of Chronic Stress and Substance Use Disorders. Cells 14: 1014. https://doi.org/10.3390/cells14131014
|
| [147] |
da Silva MCM, Iglesias LP, Candelario-Jalil E, et al. (2023) Role of Microglia in Psychostimulant Addiction. Curr Neuropharmacol 21: 235-259. https://doi.org/10.2174/1570159X21666221208142151
|
| [148] |
Avolio E, Fazzari G, Mele M, et al. (2017) Unpredictable Chronic Mild Stress Paradigm Established Effects of Pro- and Anti-inflammatory Cytokine on Neurodegeneration-Linked Depressive States in Hamsters with Brain Endothelial Damages. Mol Neurobiol 54: 6446-6458. https://doi.org/10.1007/s12035-016-0171-1
|
| [149] |
Farooq RK, Isingrini E, Tanti A, et al. (2012) Is unpredictable chronic mild stress (UCMS) a reliable model to study depression-induced neuroinflammation?. Behav Brain Res 231: 130-137. https://doi.org/10.1016/j.bbr.2012.03.020
|
| [150] |
Xia X, Li K, Zou W, et al. (2025) The central role of microglia in major depressive disorder and its potential as a therapeutic target. Front Behav Neurosci 19: 1598178. https://doi.org/10.3389/fnbeh.2025.1598178
|
| [151] |
Paganin W, Signorini S (2024) Inflammatory biomarkers in depression: scoping review. BJPsych Open 10: e165. https://doi.org/10.1192/bjo.2024.787
|
| [152] |
Reemst K, Kracht L, Kotah JM, et al. (2022) Early-life stress lastingly impacts microglial transcriptome and function under basal and immune-challenged conditions. Transl Psychiatry 12: 507. https://doi.org/10.1038/s41398-022-02265-6
|
| [153] |
Jamil S, Raza ML, Moradikor N, et al. (2025) Early life stress and brain development: Neurobiological and behavioral effects of chronic stress. Prog Brain Res 291: 49-79. https://doi.org/10.1016/bs.pbr.2025.01.004
|
| [154] | Gongwer MW, Etienne F, Moca EN, et al. (2025) Microglia regulate nucleus accumbens synaptic development and circuit function underlying threat avoidance behaviors. Res Sq 22: rs.3.rs-5837701. https://doi.org/10.1101/2025.01.15.633068 |
| [155] |
Smith JA, Das A, Ray SK, et al. (2012) Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases. Brain Res Bull 87: 10-20. https://doi.org/10.1016/j.brainresbull.2011.10.004
|
| [156] |
Lull ME, Block ML (2010) Microglial activation and chronic neurodegeneration. Neurotherapeutics 7: 354-365. https://doi.org/10.1016/j.nurt.2010.05.014
|
| [157] |
Thrailkill EA, Daniels CW (2024) The temporal structure of goal-directed and habitual operant behavior. J Exp Anal Behav 121: 38-51. https://doi.org/10.1002/jeab.896
|
| [158] |
Delgado L, Navarrete M (2023) Shining the Light on Astrocytic Ensembles. Cells 12: 1253. https://doi.org/10.3390/cells12091253
|
| [159] |
Shirokova OM, Kuzmina DM, Zaborskaya OG, et al. (2025) The Long-Term Effects of Chronic Unpredictable Mild Stress Experienced During Adolescence Could Vary Depending on Biological Sex. Int J Mol Sci 26: 1251. https://doi.org/10.3390/ijms26031251
|
| [160] |
Bergamini G, Mechtersheimer J, Azzinnari D, et al. (2018) Chronic social stress induces peripheral and central immune activation, blunted mesolimbic dopamine function, and reduced reward-directed behaviour in mice. Neurobiol Stress 8: 42-56. https://doi.org/10.1016/j.ynstr.2018.01.004
|
| [161] |
Nusslock R, Alloy LB, Brody GH, et al. (2024) Annual Research Review: Neuroimmune network model of depression: a developmental perspective. J Child Psychol Psychiatry 65: 538-567. https://doi.org/10.1111/jcpp.13961
|
| [162] |
Cervetto C, Venturini A, Guidolin D, et al. (2018) Homocysteine and A2A-D2 Receptor-Receptor Interaction at Striatal Astrocyte Processes. J Mol Neurosci 65: 456-466. https://doi.org/10.1007/s12031-018-1120-4
|
| [163] |
Wright WJ, Dong Y (2020) Psychostimulant-Induced Adaptations in Nucleus Accumbens Glutamatergic Transmission. Cold Spring Harb Perspect Med 10: a039255. https://doi.org/10.1101/cshperspect.a039255
|
| [164] |
Williams Ph DM, Cox B, Lafuse Ph DW, et al. (2019) Epstein-Barr Virus dUTPase Induces Neuroinflammatory Mediators: Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Clin Ther 41: 848-863. https://doi.org/10.1016/j.clinthera.2019.04.009
|
| [165] |
Dobryakova E, Genova HM, DeLuca J, et al. (2015) The dopamine imbalance hypothesis of fatigue in multiple sclerosis and other neurological disorders. Front Neurol 6: 52. https://doi.org/10.3389/fneur.2015.00052
|
| [166] |
Volkow ND, Wang GJ, Newcorn JH, et al. (2011) Motivation deficit in ADHD is associated with dysfunction of the dopamine reward pathway. Mol Psychiatry 16: 1147-1154. https://doi.org/10.1038/mp.2010.97
|
| [167] |
Vandenbark AA, Offner H, Matejuk S, et al. (2021) Microglia and astrocyte involvement in neurodegeneration and brain cancer. J Neuroinflammation 18: 298. https://doi.org/10.1186/s12974-021-02355-0
|
| [168] |
Kanthasamy A, Jin H, Charli A, et al. (2019) Environmental neurotoxicant-induced dopaminergic neurodegeneration: a potential link to impaired neuroinflammatory mechanisms. Pharmacol Ther 197: 61-82. https://doi.org/10.1016/j.pharmthera.2019.01.001
|
| [169] |
Wang J, Wang F, Mai D, et al. (2020) Molecular Mechanisms of Glutamate Toxicity in Parkinson's Disease. Front Neurosci 14: 585584. https://doi.org/10.3389/fnins.2020.585584
|
| [170] |
Kamath T, Abdulraouf A, Burris SJ, et al. (2022) Single-cell genomic profiling of human dopamine neurons identifies a population that selectively degenerates in Parkinson's disease. Nat Neurosci 25: 588-595. https://doi.org/10.1038/s41593-022-01061-1
|
| [171] |
Sportelli L, Eisenberg DP, Passiatore R, et al. (2024) Dopamine signaling enriched striatal gene set predicts striatal dopamine synthesis and physiological activity in vivo. Nat Commun 15: 3342. https://doi.org/10.1038/s41467-024-47456-5
|
| [172] |
Voicu V, Toader C, Serban M, et al. (2025) Systemic Neurodegeneration and Brain Aging: Multi-Omics Disintegration, Proteostatic Collapse, and Network Failure Across the CNS. Biomedicines 13: 2025. https://doi.org/10.3390/biomedicines13082025
|
| [173] |
Stevenson R, Samokhina E, Rossetti I, et al. (2020) Neuromodulation of Glial Function During Neurodegeneration. Front Cell Neurosci 14: 278. https://doi.org/10.3389/fncel.2020.00278
|
| [174] |
Jiang Q, Liu J, Huang S, et al. (2025) Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances. Signal Transduct Target Ther 10: 76. https://doi.org/10.1038/s41392-025-02145-7
|
| [175] |
Li K, Li J, Zheng J, et al. (2019) Reactive Astrocytes in Neurodegenerative Diseases. Aging Dis 10: 664-675. https://doi.org/10.14336/AD.2018.0720
|
| [176] |
Lee HG, Lee JH, Flausino LE, et al. (2023) Neuroinflammation: An astrocyte perspective. Sci Transl Med 15: eadi7828. https://doi.org/10.1126/scitranslmed.adi7828
|
| [177] |
Liddelow SA, Guttenplan KA, Clarke LE, et al. (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541: 481-487. https://doi.org/10.1038/nature21029
|
| [178] |
Garland EF, Hartnell IJ, Boche D (2022) Microglia and Astrocyte Function and Communication: What Do We Know in Humans?. Front Neurosci 16: 824888. https://doi.org/10.3389/fnins.2022.824888
|
| [179] |
Zhang Z, Niu K, Huang T, et al. (2025) Microglia depletion reduces neurodegeneration and remodels extracellular matrix in a mouse Parkinson's disease model triggered by alpha-synuclein overexpression. NPJ Parkinsons Dis 11: 15. https://doi.org/10.1038/s41531-024-00846-4
|
| [180] |
Thi Lai T, Kim YE, Nguyen LTN, et al. (2024) Microglial inhibition alleviates alpha-synuclein propagation and neurodegeneration in Parkinson's disease mouse model. NPJ Parkinsons Dis 10: 32. https://doi.org/10.1038/s41531-024-00640-2
|
| [181] |
Sunna S, Bowen CA, Ramelow CC, et al. (2023) Advances in proteomic phenotyping of microglia in neurodegeneration. Proteomics 23: e2200183. https://doi.org/10.1002/pmic.202200183
|
| [182] |
Li Z, Xu P, Deng Y, et al. (2024) M1 Microglia-Derived Exosomes Promote A1 Astrocyte Activation and Aggravate Ischemic Injury via circSTRN3/miR-331-5p/MAVS/NF-kappaB Pathway. J Inflamm Res 17: 9285-9305. https://doi.org/10.2147/JIR.S485252
|
| [183] |
Guo M, Guan A, Zhang M, et al. (2025) Exosome-mediated microglia-astrocyte interactions drive neuroinflammation in Parkinson's disease with Peli1 as a potential therapeutic target. Pharmacol Res 219: 107908. https://doi.org/10.1016/j.phrs.2025.107908
|
| [184] |
Buoso C, Seifert M, Lang M, et al. (2024) Dopamine‑iron homeostasis interaction rescues mitochondrial fitness in Parkinson's disease. Neurobiol Dis 196: 106506. https://doi.org/10.1016/j.nbd.2024.106506
|
| [185] |
Nicholson KJ, Gilliland TM, Winkelstein BA (2014) Upregulation of GLT-1 by treatment with ceftriaxone alleviates radicular pain by reducing spinal astrocyte activation and neuronal hyperexcitability. J Neurosci Res 92: 116-129. https://doi.org/10.1002/jnr.23295
|
| [186] |
Abulseoud OA, Alasmari F, Hussein AM, et al. (2022) Ceftriaxone as a Novel Therapeutic Agent for Hyperglutamatergic States: Bridging the Gap Between Preclinical Results and Clinical Translation. Front Neurosci 16: 841036. https://doi.org/10.3389/fnins.2022.841036
|
| [187] |
Jiao L, Li X, Luo Y, et al. (2022) Iron metabolism mediates microglia susceptibility in ferroptosis. Front Cell Neurosci 16: 995084. https://doi.org/10.3389/fncel.2022.995084
|
| [188] |
Ru Q, Li Y, Chen L, et al. (2024) Iron homeostasis and ferroptosis in human diseases: mechanisms and therapeutic prospects. Signal Transduct Target Ther 9: 271. https://doi.org/10.1038/s41392-024-01969-z
|
| [189] |
Rudroff T (2024) Decoding Post-Viral Fatigue: The Basal Ganglia's Complex Role in Long-COVID. Neurol Int 16: 380-393. https://doi.org/10.3390/neurolint16020028
|
| [190] |
Khan S AY, Kazi N, Sideeque S, et al. (2025) Brain structural and functional alteration in movement disorders: A narrative review of markers and their dynamic changes. NeuroMarkers 2025: 100130. https://doi.org/10.1016/j.neumar.2025.100130
|
| [191] |
Mancini M, Natoli S, Gardoni F, et al. (2023) Dopamine Transmission Imbalance in Neuroinflammation: Perspectives on Long-Term COVID-19. Int J Mol Sci 24: 5618. https://doi.org/10.3390/ijms24065618
|
| [192] |
Adamu A, Li S, Gao F, et al. (2024) The role of neuroinflammation in neurodegenerative diseases: current understanding and future therapeutic targets. Front Aging Neurosci 16: 1347987. https://doi.org/10.3389/fnagi.2024.1347987
|
| [193] |
Kanberg N, Simren J, Eden A, et al. (2021) Neurochemical signs of astrocytic and neuronal injury in acute COVID-19 normalizes during long-term follow-up. EBioMedicine 70: 103512. https://doi.org/10.1016/j.ebiom.2021.103512
|
| [194] |
Vrettou CS, Vassiliou AG, Keskinidou C, et al. (2024) A Prospective Study on Neural Biomarkers in Patients with Long-COVID Symptoms. J Pers Med 14: 313. https://doi.org/10.3390/jpm14030313
|
| [195] |
Picca A, Ferri E, Calvani R, et al. (2022) Age-Associated Glia Remodeling and Mitochondrial Dysfunction in Neurodegeneration: Antioxidant Supplementation as a Possible Intervention. Nutrients 14: 2406. https://doi.org/10.3390/nu14122406
|
| [196] |
Trist BG, Hare DJ, Double KL (2019) Oxidative stress in the aging substantia nigra and the etiology of Parkinson's disease. Aging Cell 18: e13031. https://doi.org/10.1111/acel.13031
|
| [197] |
Zhang S, Zhang C, Zhang Y, et al. (2025) Unraveling the role of neuregulin-mediated astrocytes-OPCs axis in the pathogenesis of age-related macular degeneration and Parkinson's disease. Sci Rep 15: 7352. https://doi.org/10.1038/s41598-025-92103-8
|
| [198] |
Iba M, Lee YJ, Horan-Portelance L, et al. (2025) Microglial and neuronal fates following inhibition of CSF-1R in synucleinopathy mouse model. Brain Behav Immun 123: 254-269. https://doi.org/10.1016/j.bbi.2024.09.016
|
| [199] |
Stoll AC, Kemp CJ, Patterson JR, et al. (2024) Alpha-synuclein inclusion responsive microglia are resistant to CSF1R inhibition. J Neuroinflammation 21: 108. https://doi.org/10.1186/s12974-024-03108-5
|
| [200] |
Eo H, Kim S, Jung UJ, et al. (2024) Alpha-Synuclein and Microglia in Parkinson's Disease: From Pathogenesis to Therapeutic Prospects. J Clin Med 13: 7243. https://doi.org/10.3390/jcm13237243
|
| [201] |
Guo M, Wang J, Zhao Y, et al. (2020) Microglial exosomes facilitate alpha-synuclein transmission in Parkinson's disease. Brain 143: 1476-1497. https://doi.org/10.1093/brain/awaa090
|
| [202] |
Jiao D, Yang Y, Wang K, et al. (2025) Ferroptosis: a novel pathogenesis and therapeutic strategies for Parkinson disease: A review. Medicine (Baltimore) 104: e41218. https://doi.org/10.1097/MD.0000000000041218
|
| [203] |
Tang S, Zhang J, Chen J, et al. (2025) Ferroptosis in neurodegenerative diseases: potential mechanisms of exercise intervention. Front Cell Dev Biol 13: 1622544. https://doi.org/10.3389/fcell.2025.1622544
|
| [204] | Zhi H, Wang X, Chen Y, et al. (2025) Ceftriaxone affects ferroptosis and alleviates glial cell activation in Parkinson's disease. Int J Mol Med 55: 85. https://doi.org/10.3892/ijmm.2025.5526 |
| [205] |
Chotibut T, Meadows S, Kasanga EA, et al. (2017) Ceftriaxone reduces L-dopa-induced dyskinesia severity in 6-hydroxydopamine parkinson's disease model. Mov Disord 32: 1547-1556. https://doi.org/10.1002/mds.27077
|
| [206] |
Greene C, Connolly R, Brennan D, et al. (2024) Blood-brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment. Nat Neurosci 27: 421-432. https://doi.org/10.1038/s41593-024-01576-9
|
| [207] |
Popa E, Popa AE, Poroch M, et al. (2025) The Molecular Mechanisms of Cognitive Dysfunction in Long COVID: A Narrative Review. Int J Mol Sci 26: 5102. https://doi.org/10.3390/ijms26115102
|
| [208] |
Bhatia TN, Jamenis AS, Abbas M, et al. (2023) A 14-day pulse of PLX5622 modifies alpha-synucleinopathy in preformed fibril-infused aged mice of both sexes. Neurobiol Dis 184: 106196. https://doi.org/10.1016/j.nbd.2023.106196
|
| [209] |
Yun SP, Kam TI, Panicker N, et al. (2018) Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson's disease. Nat Med 24: 931-938. https://doi.org/10.1038/s41591-018-0051-5
|
| [210] |
Li M, Chen M, Li H, et al. (2024) Glial cells improve Parkinson's disease by modulating neuronal function and regulating neuronal ferroptosis. Front Cell Dev Biol 12: 1510897. https://doi.org/10.3389/fcell.2024.1510897
|
| [211] |
Chen X, Zhang G, Liu M, et al. (2025) New perspectives on molecular mechanisms underlying exercise-induced benefits in Parkinson's disease. NPJ Parkinsons Dis 11: 256. https://doi.org/10.1038/s41531-025-01113-w
|
| [212] |
Luthra NS, Mehta N, Munoz MJ, et al. (2025) Aerobic exercise-induced changes in fluid biomarkers in Parkinson's disease. NPJ Parkinsons Dis 11: 190. https://doi.org/10.1038/s41531-025-01042-8
|
| [213] |
Hein ZM, Thazin, Kumar S, et al. (2025) Immunomodulatory Mechanisms Underlying Neurological Manifestations in Long COVID: Implications for Immune-Mediated Neurodegeneration. Int J Mol Sci 26: 6214. https://doi.org/10.3390/ijms26136214
|
| [214] |
Huang M, Long A, Hao L, et al. (2025) Astrocyte in Neurological Disease: Pathogenesis and Therapy. MedComm (2020) 6: e70299. https://doi.org/10.1002/mco2.70299
|
| [215] |
Todd AC, Hardingham GE (2020) The Regulation of Astrocytic Glutamate Transporters in Health and Neurodegenerative Diseases. Int J Mol Sci 21: 9607. https://doi.org/10.3390/ijms21249607
|
| [216] |
Naffaa MM (2025) Monoamine Oxidase B in Astrocytic GABA Synthesis: A Central Mechanism in Neurodegeneration and Neuroinflammation. J Cell Signal 6: 53-70. https://doi.org/10.33696/Signaling.6.134
|
| [217] |
Villemagne VL, Harada R, Dore V, et al. (2022) First-in-Humans Evaluation of (18)F-SMBT-1, a Novel (18)F-Labeled Monoamine Oxidase-B PET Tracer for Imaging Reactive Astrogliosis. J Nucl Med 63: 1551-1559. https://doi.org/10.2967/jnumed.121.263254
|
| [218] |
Bellaver B, Povala G, Ferreira PCL, et al. (2023) Astrocyte reactivity influences amyloid-beta effects on tau pathology in preclinical Alzheimer's disease. Nat Med 29: 1775-1781. https://doi.org/10.1038/s41591-023-02380-x
|
| [219] |
Kong Y, Cao L, Wang J, et al. (2024) In vivo reactive astrocyte imaging using [(18)F]SMBT-1 in tauopathy and familial Alzheimer's disease mouse models: A multi-tracer study. J Neurol Sci 462: 123079. https://doi.org/10.1016/j.jns.2024.123079
|
| [220] |
Chatzipieris FP, Kokkalis A, Georgiou N, et al. (2025) New Prospects in the Inhibition of Monoamine Oxidase‑B (MAO-B) Utilizing Propargylamine Derivatives for the Treatment of Alzheimer's Disease: A Review. ACS Omega 10: 26208-26232. https://doi.org/10.1021/acsomega.5c00134
|
| [221] |
Zou DJ, Liu RZ, Lv YJ, et al. (2024) Chromone-deferiprone hybrids as novel MAO-B inhibitors and iron chelators for the treatment of Alzheimer's disease. Org Biomol Chem 22: 6189-6197. https://doi.org/10.1039/D4OB00919C
|
| [222] |
Duta C, Muscurel C, Dogaru CB, et al. (2024) Ferroptosis-A Shared Mechanism for Parkinson's Disease and Type 2 Diabetes. Int J Mol Sci 25: 8838. https://doi.org/10.3390/ijms25168838
|
| [223] |
Liu S, Gao X, Zhou S (2022) New Target for Prevention and Treatment of Neuroinflammation: Microglia Iron Accumulation and Ferroptosis. ASN Neuro 14: 17590914221133236. https://doi.org/10.1177/17590914221133236
|
| [224] |
Xu Y, Jia B, Li J, et al. (2024) The Interplay between Ferroptosis and Neuroinflammation in Central Neurological Disorders. Antioxidants (Basel) 13: 395. https://doi.org/10.3390/antiox13040395
|
| [225] |
Feng S, Tang D, Wang Y, et al. (2023) The mechanism of ferroptosis and its related diseases. Mol Biomed 4: 33. https://doi.org/10.1186/s43556-023-00142-2
|
| [226] |
Oh SJ, Ahn H, Jung KH, et al. (2020) Evaluation of the Neuroprotective Effect of Microglial Depletion by CSF-1R Inhibition in a Parkinson's Animal Model. Mol Imaging Biol 22: 1031-1042. https://doi.org/10.1007/s11307-020-01485-w
|
| [227] |
Ho MS (2025) Clearance Pathways for alpha-Synuclein in Parkinson's Disease. J Neurochem 169: e70124. https://doi.org/10.1111/jnc.70124
|
| [228] |
Basilico B, Ferrucci L, Khan A, et al. (2022) What microglia depletion approaches tell us about the role of microglia on synaptic function and behavior. Front Cell Neurosci 16: 1022431. https://doi.org/10.3389/fncel.2022.1022431
|
| [229] | Adaikkan C RIM, Lorenzo Bozzelli P, Sears M, et al. (2025) A multimodal approach of microglial CSF1R inhibition and GENUS provides therapeutic effects in Alzheimer's disease mice. bioRxiv . https://doi.org/10.1101/2025.04.27.648471 |
| [230] |
Noh MY, Kwon HS, Kwon MS, et al. (2025) Biomarkers and therapeutic strategies targeting microglia in neurodegenerative diseases: current status and future directions. Mol Neurodegener 20: 82. https://doi.org/10.1186/s13024-025-00867-4
|
| [231] |
Taguchi D, Ehara A, Kadowaki T, et al. (2020) Minocycline Alleviates Cluster Formation of Activated Microglia and Age-dependent Dopaminergic Cell Death in the Substantia Nigra of Zitter Mutant Rat. Acta Histochem Cytochem 53: 139-146. https://doi.org/10.1267/ahc.20-00022
|
| [232] |
Griffin JM, Fackelmeier B, Fong DM, et al. (2019) Astrocyte-selective AAV gene therapy through the endogenous GFAP promoter results in robust transduction in the rat spinal cord following injury. Gene Ther 26: 198-210. https://doi.org/10.1038/s41434-019-0075-6
|
| [233] |
Van Den Herrewegen Y, Sanderson TM, Sahu S, et al. (2021) Side-by-side comparison of the effects of Gq- and Gi-DREADD-mediated astrocyte modulation on intracellular calcium dynamics and synaptic plasticity in the hippocampal CA1. Mol Brain 14: 144. https://doi.org/10.1186/s13041-021-00856-w
|
| [234] |
Zhong X, Gu H, Lim J, et al. (2025) Genetically encoded sensors illuminate in vivo detection for neurotransmission: Development, application, and optimization strategies. IBRO Neurosci Rep 18: 476-490. https://doi.org/10.1016/j.ibneur.2025.03.003
|
| [235] |
Harada R, Hayakawa Y, Ezura M, et al. (2021) (18)F-SMBT-1: A Selective and Reversible PET Tracer for Monoamine Oxidase-B Imaging. J Nucl Med 62: 253-258. https://doi.org/10.2967/jnumed.120.244400
|
| [236] |
Mishra S, Gordon BA, Su Y, et al. (2017) AV-1451 PET imaging of tau pathology in preclinical Alzheimer disease: Defining a summary measure. Neuroimage 161: 171-178. https://doi.org/10.1016/j.neuroimage.2017.07.050
|
| [237] |
Zhang M, Qian XH, Hu J, et al. (2024) Integrating TSPO PET imaging and transcriptomics to unveil the role of neuroinflammation and amyloid-beta deposition in Alzheimer's disease. Eur J Nucl Med Mol Imaging 51: 455-467. https://doi.org/10.1007/s00259-023-06446-3
|
| [238] |
Bonomi CG, Chiaravalloti A, Camedda R, et al. (2023) Functional Correlates of Microglial and Astrocytic Activity in Symptomatic Sporadic Alzheimer's Disease: A CSF/(18)F-FDG-PET Study. Biomedicines 11: 725. https://doi.org/10.3390/biomedicines11030725
|
| [239] |
Ballweg A, Klaus C, Vogler L, et al. (2023) [(18)F]F-DED PET imaging of reactive astrogliosis in neurodegenerative diseases: preclinical proof of concept and first-in-human data. J Neuroinflammation 20: 68. https://doi.org/10.1186/s12974-023-02749-2
|
| [240] |
Lin J, Ou R, Li C, et al. (2023) Plasma glial fibrillary acidic protein as a biomarker of disease progression in Parkinson's disease: a prospective cohort study. BMC Med 21: 420. https://doi.org/10.1186/s12916-023-03120-1
|
| [241] |
Shi Q, Gutierrez RA, Bhat MA (2025) Microglia, Trem2, and Neurodegeneration. Neuroscientist 31: 159-176. https://doi.org/10.1177/10738584241254118
|
| [242] |
Zhang L, Xiang X, Li Y, et al. (2025) TREM2 and sTREM2 in Alzheimer's disease: from mechanisms to therapies. Mol Neurodegener 20: 43. https://doi.org/10.1186/s13024-025-00834-z
|
| [243] |
Gabrielli M, Raffaele S, Fumagalli M, et al. (2022) The multiple faces of extracellular vesicles released by microglia: Where are we 10 years after?. Front Cell Neurosci 16: 984690. https://doi.org/10.3389/fncel.2022.984690
|
| [244] |
Wang P, Lan G, Xu B, et al. (2023) alpha-Synuclein-carrying astrocytic extracellular vesicles in Parkinson pathogenesis and diagnosis. Transl Neurodegener 12: 40. https://doi.org/10.1186/s40035-023-00372-y
|
| [245] |
Kopp KO, Glotfelty EJ, Li Y, et al. (2022) Glucagon-like peptide-1 (GLP-1) receptor agonists and neuroinflammation: Implications for neurodegenerative disease treatment. Pharmacol Res 186: 106550. https://doi.org/10.1016/j.phrs.2022.106550
|
| [246] |
Cheng D, Yang S, Zhao X, et al. (2022) The Role of Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RA) in Diabetes-Related Neurodegenerative Diseases. Drug Des Devel Ther 16: 665-684. https://doi.org/10.2147/DDDT.S348055
|
| [247] |
Timper K, Del Rio-Martin A, Cremer AL, et al. (2020) GLP-1 Receptor Signaling in Astrocytes Regulates Fatty Acid Oxidation, Mitochondrial Integrity, and Function. Cell Metab 31: 1189-1205 e1113. https://doi.org/10.1016/j.cmet.2020.05.001
|
| [248] |
Bayram E, Batzu L, Tilley B, et al. (2023) Clinical trials for cognition in Parkinson's disease: Where are we and how can we do better?. Parkinsonism Relat Disord 112: 105385. https://doi.org/10.1016/j.parkreldis.2023.105385
|
| [249] |
Diz-Chaves Y, Mastoor Z, Spuch C, et al. (2022) Anti-Inflammatory Effects of GLP-1 Receptor Activation in the Brain in Neurodegenerative Diseases. Int J Mol Sci 23: 9583. https://doi.org/10.3390/ijms23179583
|
| [250] |
Fan R, Xu F, Previti ML, et al. (2007) Minocycline reduces microglial activation and improves behavioral deficits in a transgenic model of cerebral microvascular amyloid. J Neurosci 27: 3057-3063. https://doi.org/10.1523/JNEUROSCI.4371-06.2007
|
| [251] |
Sriram K, Miller DB, O'Callaghan JP (2006) Minocycline attenuates microglial activation but fails to mitigate striatal dopaminergic neurotoxicity: role of tumor necrosis factor-alpha. J Neurochem 96: 706-718. https://doi.org/10.1111/j.1471-4159.2005.03566.x
|
Figures(5) / Tables(5)
Moawiah M Naffaa. Glial-Dopamine crosstalk: Astrocytic and microglial gatekeepers of neuroinflammation, plasticity, and motivation[J]. AIMS Neuroscience, 2026, 13(1): 64-118. doi: 10.3934/Neuroscience.2026004
DownLoad: