Cortical and Striatal Circuits in Huntington's Disease.

Sonja Blumenstock,Irina Dudanova

doi:10.3389/fnins.2020.00082

Sonja Blumenstock, Irina Dudanova

Open Access

https://doi.org/10.3389/fnins.2020.00082

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Abstract

Huntington’s disease (HD) is a hereditary neurodegenerative disorder that typically manifests in midlife with motor, cognitive, and/or psychiatric symptoms. The disease is caused by a CAG triplet expansion in exon 1 of the huntingtin gene and leads to a severe neurodegeneration in the striatum and cortex. Classical electrophysiological studies in genetic HD mouse models provided important insights into the disbalance of excitatory, inhibitory and neuromodulatory inputs, as well as progressive disconnection between the cortex and striatum. However, the involvement of local cortical and striatal microcircuits still remains largely unexplored. Here we review the progress in understanding HD-related impairments in the cortical and basal ganglia circuits, and outline new opportunities that have opened with the development of modern circuit analysis methods. In particular, in vivo imaging studies in mouse HD models have demonstrated early structural and functional disturbances within the cortical network, and optogenetic manipulations of striatal cell types have started uncovering the causal roles of certain neuronal populations in disease pathogenesis. In addition, the important contribution of astrocytes to HD-related circuit defects has recently been recognized. In parallel, unbiased systems biology studies are providing insights into the possible molecular underpinnings of these functional defects at the level of synaptic signaling and neurotransmitter metabolism. With these approaches, we can now reach a deeper understanding of circuit-based HD mechanisms, which will be crucial for the development of effective and targeted therapeutic strategies.

Highlights

Huntington’s disease (HD) is a devastating movement disorder that affects about 1 in 10,000 people
It should be noted that this simple model of two antagonistic striatal pathways has been refined in the recent years by in vivo studies demonstrating simultaneous activation of dSPN and iSPN cell clusters during motion initiation, as well as similar correlation of their activity with locomotor behavior, suggesting a more sophisticated functional arrangement of basal ganglia circuits than previously thought (Cui et al, 2013; Barbera et al, 2016; Klaus et al, 2017; Parker et al, 2018)
The conclusion that emerged from electrophysiological studies in slices as well as in vivo in multiple HD mouse models is that alterations in corticostriatal connections occur in two phases, with increased glutamate release and spiny projection neurons (SPNs) hyperexcitation at the presymptomatic stage, followed by SPN silencing at the symptomatic stage (Figure 3) (Klapstein et al, 2001; Cepeda et al, 2003; Rebec et al, 2006; Joshi et al, 2009; André et al, 2011b; Miller et al, 2011; Raymond et al, 2011; Indersmitten et al, 2015; Rothe et al, 2015)

Summary

Introduction

Huntington’s disease (HD) is a devastating movement disorder that affects about 1 in 10,000 people. Changes in neuronal function occur long before overt cell death is observed, suggesting that circuit alterations underlie the early symptoms of the disease.

Results

Conclusion