Cytokine and Chemokine Alterations in Down Syndrome

Abstract

Objective Down syndrome (DS) is the leading genetic cause of intellectual disability, affecting ~1/800 newborns. Previously we have shown alterations in N-methyl-D-aspartic acid (NMDA) receptors and neuropeptides (activity-dependant neuroprotective protein, glia fibrillary acidic protein) in a murine model of DS. Cytokines and chemokines have neuromodulatory and neurotransmitter roles and interact with the NMDA receptors. The objective of this study was to evaluate if cytokines and chemokines in the hippocampus and cerebellum are altered in this model.

Study Design We used 8- to 10-month-old animals from the well-characterized mouse model of DS (Ts65Dn). Learning and memory were assessed in the Morris water maze with the Ts65Dn animals demonstrating a learning deficit. After completion of the behavioral testing, the brains were removed and the hippocampus and cerebellum were separated by microdissection. A panel of cytokines, chemokines, and fractalkine were measured in the protein lysates using a microsphere-based multiplex immunoassay (Luminex xMAP, Millipore) and normalized to total protein concentration. Statistical analysis included the nonparametric Mann-Whitney U for the cytokine, chemokine, and fractalkine levels; p < 0.05 was considered significant.

Results Levels (median [range]) of interleukin (IL)-1β (6.95 [0.11 to 43.5] versus 14.2 [0.2 to 36.8] pg/mL); granulocyte-macrophage colony-stimulating factor (GM-CSF; 3.97 [0.19 to 19.6] versus 19.2 [0.2 to 31.1] pg/mL), and macrophage inflammatory protein (MIP)-1α (20.3 [0.11 to 73.3] versus 37.0 [0.22 to 102.7] pg/mL) in the hippocampus from Ts65Dn were significantly lower compared with the euploid (control) animals. Many cytokines and chemokines were not detected in the hippocampus or cerebellum, and others were detectable but not different between the groups.

Conclusion We found a decreased in GM-CSF, IL-1β, and MIP-1α in the hippocampus of DS pups. All three have known interactions with NMDA receptors and their decline may explain, in part, the learning deficits associated with DS.

Keywords

down syndrome - cytokine - chemokine learning

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