Dysfunctional striatal dopamine signaling in Huntington's disease

Abstract

Dopamine signaling in the striatum is critical for a variety of behaviors including movement, behavioral flexibility, response to reward and many forms of learning. Alterations to dopamine transmission contribute to pathological features of many neurological diseases, including Huntington's disease (HD). HD is an autosomal dominant genetic disorder caused by a CAG repeat expansion in the Huntingtin gene. The striatum is preferentially degenerated in HD, and this region receives dopaminergic input from the substantia nigra. Studies of HD patients and genetic rodent models have shown changes to levels of dopamine and its receptors in the striatum, and alterations in dopamine receptor signaling and modulation of other neurotransmitters, notably glutamate. Throughout his career, Dr. Michael Levine's research has furthered our understanding of dopamine signaling in the striatum of healthy rodents and HD mouse models. This review will focus on the work of his group and others in elucidating alterations to striatal dopamine signaling that contribute to pathophysiology in HD mouse models, and how these findings relate to human HD studies. We will also discuss current and potential therapeutic interventions for HD that target the dopamine system, and future research directions for this field.

Corticostriatal synaptic plasticity alterations in the R6/1 transgenic mouse model of Huntington's disease

“…Understanding the D 1 R‐ and D 2 R‐dependent mechanisms of tardive degeneration of the striatal function in symptomatic HD is currently an urgent need in clinical research. Despite the difficulties to translate insights from animal models into clinical settings, it is crucial to design new therapeutic strategies that integrate multiple approaches focusing on DA modulation as a promising option (Cepeda, Murphy, Parent, & Levine, ; Koch & Raymond, ) to ease a complex management of the triad of motor, cognitive, and psychiatric symptoms in HD patients.…”

D1R- and D2R-Medium-Sized Spiny Neurons Diversity: Insights Into Striatal Vulnerability to Huntington’s Disease Mutation

“…Mutant HTT mRNA sequesters spliceosome components, dysregulating splicing, and causing toxicity g Sathasivam et al, 2013;Lin et al, 2016;Schilling et al, 2019 Epigenetics Preferentially closed chromatin state and transcriptional repression: reduced histone acetylation, increased histone methylation e,f , decreased AcH3 levels, decreased number of genes bound by AcH3 f , increased H3K27me3 and decreased H3K4me3 e Ferrante et al, 2003;Stack et al, 2007;Luthi-Carter et al, 2010;Seong et al, 2010;McFarland et al, 2012;Biagioli et al, 2015;Hervás-Corpión, 2018;Pearl et al, 2020 Dopamine signaling b Altered dopamine signaling has been associated with behavioral alterations observed in HD. Dopamine levels are increased at early stage and decreased at later stage Chen et al, 2013;Koch and Raymond, 2019 Somatic CAG instability b Increased in striatum and cerebral cortex Telenius et al, 1994;Swami et al, 2009 Electrophysiology d Changes in the balance of excitatory and inhibitory inputs to the direct and indirect pathway MSNs Galvan et al, 2012 *Abbreviations are indicated with superscript numbers, models used in the studies with superscript letters. 1 Brain-derived neurotrophic factor-tropomyosin-related kinase receptor type B.…”

“…This might be due to the inhibitory effect of MSNs projecting to the SNc, which, in early stages, may produce hyperactivation of this pathway. Conversely, as disease progresses, dopamine levels decreasepossibly because of dopaminergic nigrostriatal terminals lossaccounting for the late akinetic stage (Chen et al, 2013;Koch and Raymond, 2019 ; Table 1). Accordingly, studies on both patients and mouse models confirmed an increase in dopamine release and tyrosine hydroxylase levels in early HD, followed by a reduction of the same parameters in advanced disease conditions (Koch and Raymond, 2019).…”

Cortical and Striatal Circuits in Huntington’s Disease

“…The dopaminergic circuit anatomy as well as dopaminergic signaling alterations in HD are described in detail in a number of excellent articles (André et al, 2010;Gerfen and Surmeier, 2011;Tritsch and Sabatini, 2012;Chen et al, 2013;Gardoni and Bellone, 2015;Rangel-Barajas and Rebec, 2016;Koch and Raymond, 2019). Two major dopaminergic pathways that innervate cortical and striatal areas and both show alterations in HD are the nigrostriatal and mesocorticolimbic pathways.…”

“…The early symptomatic stage characterized by chorea is reflected by excessive glutamate and DA release, leading to a selective activation of the direct pathway and disinhibition of the thalamus. At a later stage, when chorea is replaced by hypoactivity, a lack of sufficient glutamate and DA signaling leads to the silencing of the direct pathway and inhibition of the thalamus (Johnson et al, 2006;Joshi et al, 2009;André et al, 2010André et al, , 2011bCallahan and Abercrombie, 2011;Galvan et al, 2012;Rothe et al, 2015;Covey et al, 2016;Koch and Raymond, 2019).…”