Jul 7, 2020

Reduced Fractalkine Levels Lead to Striatal Synaptic Plasticity Deficits in Huntington's Disease

Frontiers in Cellular Neuroscience
Anya KimManuel J Rodríguez

Abstract

Huntington's disease (HD) is an inherited neurodegenerative disorder in which the striatum is the most affected brain region. Although a chronic inflammatory microglial reaction that amplifies disease progression has been described in HD patients, some murine models develop symptoms without inflammatory microglial activation. Thus, dysfunction of non-inflammatory microglial activity could also contribute to the early HD pathological process. Here, we show the involvement of microglia and particularly fractalkine signaling in the striatal synaptic dysfunction of R6/1 mice. We found reduced fractalkine gene expression and protein concentration in R6/1 striata from 8 to 20 weeks of age. Consistently, we also observed a down-regulation of fractalkine levels in the putamen of HD patients and in HD patient hiPSC-derived neurons. Automated cell morphology analysis showed a non-inflammatory ramified microglia in the striatum of R6/1 mice. However, we found increased PSD-95-positive puncta inside microglia, indicative of synaptic pruning, before HD motor symptoms start to manifest. Indeed, microglia appeared to be essential for striatal synaptic function, as the inhibition of microglial activity with minocycline impaired the induction o...Continue Reading

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Mentioned in this Paper

Structure of Putamen
Corpus Striatum Structure
Mental Depression
Synapses
Microglia
Analysis
Laboratory mice
Microglial Cell Activation
Presynaptic density protein 95
Synaptic Membranes

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