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Dopamine and glutamate in Huntington's disease: A balancing act
Véronique M André1, Carlos Cepeda, Michael S Levine
1Intellectual and Developmental Disabilities Research Center, Semel Institute, Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, USA. vandre@mednet.ucla.edu <vandre@mednet.ucla.edu>
Insights
Huntington's disease (HD) involves CAG repeat expansion, affecting dopamine (DA) and glutamate neurotransmission. Restoring the balance between these neurotransmitters may help treat HD symptoms.
Area of Science:
- Neuroscience
- Genetics
- Neurology
Background:
- Huntington's disease (HD) is a genetic neurodegenerative disorder caused by a CAG repeat expansion in the HD gene.
- The mutation leads to polyglutamine tract expansion in the huntingtin protein, causing progressive motor and cognitive decline.
- Pathological hallmarks include neurodegeneration in the basal ganglia and cortex, with complex alterations in neurotransmitter systems.
Purpose of the Study:
- To review evidence on dopamine-glutamate interactions in Huntington's disease.
- To examine how these interactions change in the striatum and cortex during HD progression.
- To explore the potential of restoring neurotransmitter balance for therapeutic benefit.
Main Methods:
- Literature review focusing on studies investigating dopamine and glutamate neurotransmission in Huntington's disease.
- Analysis of evidence for altered neurotransmitter function in the striatum and cortex.
- Synthesis of findings related to the interplay between dopamine and glutamate in HD pathogenesis.
Main Results:
- Evidence suggests both initial increases and later decreases in dopamine (DA) and glutamate neurotransmission in HD.
- These alterations disrupt the normal balance where DA modulates glutamate-induced excitation.
- Dysfunction is particularly apparent in the basal ganglia and cortex.
Conclusions:
- Dopamine and glutamate neurotransmission are significantly affected in Huntington's disease.
- The disruption of the DA-glutamate balance contributes to HD pathophysiology.
- Therapeutic strategies aimed at re-establishing this balance may offer a promising avenue for treating HD symptoms.
Abstract:
Huntington's disease (HD) is caused by a CAG repeat expansion in exon 1 of the HD gene resulting in a long polyglutamine tract in the N-terminus of the protein huntingtin. Patients carrying the mutation display chorea in early stages followed by akinesia and sometimes dystonia in late stages. Other major symptoms include depression, anxiety, irritability or aggressive behavior, and apathy. Although many neuronal systems are affected, dysfunction and subsequent neurodegeneration in the basal ganglia and cortex are the most apparent pathologies. In HD, the primary hypothesis has been that there is an initial overactivity of glutamate neurotransmission that produces excitotoxicity followed by a series of complex changes that are different in the striatum and in the cortex. This review will focus on evidence for alterations in dopamine (DA)-glutamate interactions in HD, concentrating on the striatum and cortex. The most recent evidence points to decreases in DA and glutamate neurotransmission as the HD phenotype develops. However, there is some evidence for increased DA and glutamate functions that could be responsible for some of the early HD phenotype. Significant evidence indicates that glutamate and dopamine neurotransmission is affected in HD, compromising the fine balance in which DA modulates glutamate-induced excitation in the basal ganglia and cortex. Restoring the balance between glutamate and dopamine could be helpful to treat HD symptoms.
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