Abstract
Dopamine (DA) plays an essential role in the control of coordinated movements. Alterations in DA balance in the striatum lead to pathological conditions such as Parkinson's and Huntington's diseases (HD). HD is a progressive, invariably fatal neurodegenerative disease caused by a genetic mutation producing an expansion of glutamine repeats and is characterized by abnormal dance-like movements (chorea). The principal pathology is the loss of striatal and cortical projection neurons. Changes in brain DA content and receptor number contribute to abnormal movements and cognitive deficits in HD. In particular, during the early hyperkinetic stage of HD, DA levels are increased whereas expression of DA receptors is reduced. In contrast, in the late akinetic stage, DA levels are significantly decreased and resemble those of a Parkinsonian state. Time-dependent changes in DA transmission parallel biphasic changes in glutamate synaptic transmission and may enhance alterations in glutamate receptor-mediated synaptic activity. In this review, we focus on neuronal electrophysiological mechanisms that may lead to some of the motor and cognitive symptoms of HD and how they relate to dysfunction in DA neurotransmission. Based on clinical and experimental findings, we propose that some of the behavioral alterations in HD, including reduced behavioral flexibility, may be caused by altered DA modulatory function. Thus, restoring DA balance alone or in conjunction with glutamate receptor antagonists could be a viable therapeutic approach.
Highlights
We focus on neuronal electrophysiological mechanisms that may lead to some of the motor and cognitive symptoms of Huntington’s disease (HD) and how they relate to dysfunction in DA neurotransmission
Huntington’s disease (HD) is an inherited, autosomal dominant, and progressive neurodegenerative disorder caused by a mutation in the huntingtin gene (HTT) resulting in an abnormally long polyglutamine (CAG >40) repeat (The Huntington’s Disease Collaborative Research Group, 1993)
This review examines the role of striatal dopamine (DA) in HD
Summary
Huntington’s disease (HD) is an inherited, autosomal dominant, and progressive neurodegenerative disorder caused by a mutation in the huntingtin gene (HTT) resulting in an abnormally long polyglutamine (CAG >40) repeat (The Huntington’s Disease Collaborative Research Group, 1993). Reversal learning and trait impulsivity in mice is associated with DA receptor density in the midbrain (Dalley et al, 2007; Lee et al, 2009) Taken together, these studies indicate that the striatum and DA neurotransmission play a crucial role in determining behavioral flexibility. Robust stereotypies in rats similar to those induced by amphetamine and cocaine can be induced by striatal infusions of D1 and D2 receptor agonists (Waszczak et al, 2002) It would be misleading, to think that only DA alterations are involved in behavioral inflexibility. The capacity for attentional shifts and inhibition of ongoing motor activity by salient stimuli seems to depend on thalamostriatal inputs onto cholinergic interneurons (Ding et al, 2010) These aspiny interneurons have rich terminal connections and are implicated in stereotypic behavior as well as associative learning (Aosaki et al, 1994, 2010). It was thought that DA levels in HD may show biphasic, timedependent changes, with early increases followed by late decreases (Table 1)
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