Microglial responses to dopamine in a cell culture model of Parkinson's disease

• Published in: Neurobiology of aging 2009-11, Vol.30 (11), p.1805-1817
• Main Authors: Mastroeni, Diego, Grover, Andrew, Leonard, Brian, Joyce, Jeffrey N, Coleman, Paul D, Kozik, Brooke, Bellinger, Denise L, Rogers, Joseph
• Format: Article
• Language: English
• Subjects: Aged; Aging; Antineoplastic Agents - pharmacology; Biological and medical sciences; Brain-Derived Neurotrophic Factor - pharmacology; Cells, Cultured; Chemotaxis; Coculture Techniques - methods; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dentate Gyrus - pathology; Development. Senescence. Regeneration. Transplantation; Dopamine; Dopamine - metabolism; Dopamine - pharmacology; Dopamine Antagonists - pharmacology; Dopamine receptor; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - drug effects; Humans; Internal Medicine; Lipopolysaccharides - pharmacology; Medical sciences; Microglia; Microglia - drug effects; Neuroblastoma - pathology; Neurology; Parkinson Disease - pathology; Parkinson's disease; Potassium - pharmacology; Receptors, Dopamine - genetics; Receptors, Dopamine - metabolism; RNA, Messenger - metabolism; Spiperone - pharmacology; Substantia nigra; Tretinoin - pharmacology; Vertebrates: nervous system and sense organs
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2008.01.001

Abstract Activated microglia appear to selectively attack dopamine (DA) neurons in the Parkinson's disease (PD) substantia nigra. We investigated potential mechanisms using culture models. As targets, human SH-SY5Y cells were left undifferentiated (UNDIFF) or were differentiated with retinoic acid (RA) or RA plus brain-derived neurotrophic factor (RA/BDNF). RA/BDNF-treated cells were immunoreactive for tyrosine hydroxylase and the DA transporter, took up exogenous DA, and released DA after K+ stimulation. Undifferentiated and RA-treated cells lacked these characteristics of a DA phenotype. Co-culture of target cells with human elderly microglia resulted in elevated toxicity in DA phenotype (RA/BDNF) cells. Lipopolysaccharide (LPS) plus K+ -stimulated DA release enhanced toxicity by 500-fold. DA induced microglial chemotaxis in Boyden chambers. Spiperone inhibited this effect. Cultured human elderly microglia expressed mRNAs for D1–D4 but not D5 DA receptors. The microglia, as well as PD microglia in situ, were also immunoreactive for D1–D4 but not D5 DA receptors. These findings demonstrate that activated microglia express DA receptors, and suggest that this mechanism may play a role in the selective vulnerability of DA neurons in PD.