Patient-specific models of microglia-mediated engulfment of synapses and neural progenitors

• Published in: Molecular psychiatry Vol. 22; no. 2; pp. 170 - 177
• Main Authors: Sellgren, C M, Sheridan, S D, Gracias, J, Xuan, D, Fu, T, Perlis, R H
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2017; Nature Publishing Group
• Subjects: 631/378; 631/532; 692/699/476/1799; Aged; Aged, 80 and over; Behavioral Sciences; Biological Psychology; Brain - physiopathology; Brain research; Cell Culture Techniques; Complement C4 - metabolism; Disease; Female; Genetic research; Granulocytes; Humans; Immediate Communication; Leukocytes, Mononuclear; Male; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Microglia; Microglia - metabolism; Microglia - physiology; Models, Biological; Nervous system; Neural Stem Cells - physiology; Neurodegenerative diseases; Neurodegenerative Diseases - physiopathology; Neuronal Plasticity - physiology; Neurons; Neurosciences; Observations; Pharmacotherapy; Psychiatry; R&D; Research & development; Synapses - metabolism; Synapses - physiology; Synaptic transmission; United States > US; Massachusetts
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/mp.2016.220

Engulfment of synapses and neural progenitor cells (NPCs) by microglia is critical for the development and maintenance of proper brain circuitry, and has been implicated in neurodevelopmental as well as neurodegenerative disease etiology. We have developed and validated models of these mechanisms by reprogramming microglia-like cells from peripheral blood mononuclear cells, and combining them with NPCs and neurons derived from induced pluripotent stem cells to create patient-specific cellular models of complement-dependent synaptic pruning and elimination of NPCs. The resulting microglia-like cells express appropriate markers and function as primary human microglia, while patient-matched macrophages differ markedly. As a demonstration of disease-relevant application, we studied the role of C4, recently implicated in schizophrenia, in engulfment of synaptic structures by human microglia. The ability to create complete patient-specific cellular models of critical microglial functions utilizing samples taken during a single clinical visit will extend the ability to model central nervous system disease while facilitating high-throughput screening.