Dysregulation of Corticostriatal Connectivity in Huntington’s Disease: A Role for Dopamine Modulation

Abstract

Aberrant communication between striatum, the main information processing unit of the basal ganglia, and cerebral cortex plays a critical role in the emergence of Huntington’s disease (HD), a fatal monogenetic condition that typically strikes in the prime of life. Although both striatum and cortex undergo substantial cell loss over the course of HD, corticostriatal circuits become dysfunctional long before neurons die. Understanding the dysfunction is key to developing effective strategies for treating a progressively worsening triad of motor, cognitive, and psychiatric symptoms. Cortical output neurons drive striatal activity through the release of glutamate, an excitatory amino acid. Striatal outputs, in turn, release γ-amino butyric acid (GABA) and exert inhibitory control over downstream basal ganglia targets. Ample evidence from transgenic rodent models points to dysregulation of corticostriatal glutamate transmission along with corresponding changes in striatal GABA release as underlying factors in the HD behavioral phenotype. Another contributor is dysregulation of dopamine (DA), a modulator of both glutamate and GABA transmission. In fact, pharmacological manipulation of DA is the only currently available treatment for HD symptoms. Here, we review data from animal models and human patients to evaluate the role of DA in HD, including DA interactions with glutamate and GABA within the context of dysfunctional corticostriatal circuitry.

Integrating multimodal connectivity improves prediction of individual cognitive abilities

“…Here, we observe that structural connections between the caudate and regions in frontal, parietal, occipital, and cingulate cortices are especially important to predict crystallised and fluid cognition. This finding is consistent with the known role of corticostriatal-thalamocortical loops in healthy executive function (Seger, 2009), and in neurologic disorders (Shepherd, 2013, Leisman et al, 2013 that result in executive dysfunction such as Parkinson's disease (Zgaljardic et al, 2006) and Huntington's disease (Rangel-Barajas and Rebec, 2016).…”

Roles of the M4 acetylcholine receptor in the basal ganglia and the treatment of movement disorders

“…HD Symptoms May Be Delayed by M 4 Activation. In HD, before the onset of motor symptoms in experimental models of HD, there is excessive cortico‐striatal drive and increased DA release in the striatum of many mouse models of HD . This increased glutamatergic and DA drive eventually switches to decreased cortico‐striatal drive and decreased DA release by the time motor symptoms appear .…”

“…In HD, before the onset of motor symptoms in experimental models of HD, there is excessive cortico-striatal drive and increased DA release in the striatum of many mouse models of HD. 88,89 This increased glutamatergic and DA drive eventually switches to decreased corticostriatal drive and decreased DA release by the time motor symptoms appear. 48 This increased release of neurotransmitter may underlie or exacerbate the degeneration present in HD or could drive the circuitry changes that lead to the alterations of motor behaviors.…”

Corticostriatal network dysfunction in Huntington's disease: Deficits in neural processing, glutamate transport, and ascorbate release

“…In fact, in awake and behaving animals, dopamine appears to adjust the strength or signal‐to‐noise ratio of the glutamate‐evoked excitation . Interestingly, the only HD treatment widely available to date alters striatal dopamine transmission …”

“…38 Interestingly, the only HD treatment widely available to date alters striatal dopamine transmission. 39 In R6/2 mice, a truncated transgenic model of HD with ~150 CAG repeats and an early emerging and robust symptom profile, striatal MSN activity is significantly faster than in wild-type (WT) controls. 40 This is the case regardless of whether the mice are resting quietly, actively exploring their environment, or under general anesthesia.…”