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

Anya Kim,Mercè Masana,Andrés Miguez,Jordi Alberch,Marco Straccia,Manuel J Rodríguez,Josep M Canals,Esther García-García,Andrea Comella-Bolla

doi:10.3389/fncel.2020.00163

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 of corticostriatal long-term depression (LTD) in wild-type mice. Notably, fractalkine administration restored impaired corticostriatal LTD in R6/1 mice. Our results unveil a role for fractalkine-dependent neuron-microglia interactions in the early striatal synaptic dysfunction characteristic of HD.

Highlights

Huntington’s disease (HD) is an inherited neurodegenerative disorder characterized by motor, cognitive, and psychiatric disturbances
Since microglia have been proposed to contribute to the HD pathological process, and the FKN-CX3CR1 axis has a central role in controlling microglial activity, we first analyzed the effects of mutant huntingtin (mHtt) on CX3CR1 and FKN expression in the striatum of R6/1 mice at different ages (1, 8, 12, 20, and 30 weeks of age)
After mRNA quantification by qRT-Polymerase chain reaction (PCR), we found no CX3CR1 expression changes in the striatum of R6/1 mice when compared with WT animals at any of the ages studied (Figure 1A)

Summary

Introduction

Huntington’s disease (HD) is an inherited neurodegenerative disorder characterized by motor, cognitive, and psychiatric disturbances. Loss of corticostriatal synapses (Deng et al, 2013), altered striatal long-term depression (LTD) (Cummings et al, 2007; Creus-Muncunill et al, 2019; Ghiglieri et al, 2019) and reduction of striatal excitatory postsynaptic currents (Cepeda et al, 2003) have been described in R6/1 mice, a transgenic model of HD. This progressive corticostriatal communication impairment markedly alters basal ganglia circuitry activity, leading to motor disturbances (Hong et al, 2012; Puigdellívol et al, 2015; Veldman and Yang, 2018)

Methods

Results

Conclusion