Dopamine and glutamate in Huntington's disease: A balancing act

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.

Figure 1

Glutamate and DA in basal ganglia function in intact brain and during HD. Left is a simplified schematic showing normal basal ganglia circuitry. Glutamate inputs are represented in red, GABA in blue and DA in green. Under normal conditions (left), the thalamus is inhibited by GPi and SNr GABA projections. In early HD (middle), cortical dysfunction induces excessive glutamate release in the striatum. Abnormally elevated striatal glutamate and DA levels trigger selective dysfunction of enkephalin‐containing MSNs. Imbalance between the direct and indirect pathways induces hyperkinesia via two pathways: (1) Selective dysfunction/degeneration (dashed lines) of enkephalin‐containing MSNs leads to decreased release of GABA in the GPe and to its disinhibition. In turn, overactivation of GABA neurons of the GPe leads to increased release of GABA and to inhibition of STN which decreases glutamate release and decreases activity of the GPi and SNr. (2) Overactivation of the direct pathway MSNs (by abnormal DA modulation and/or excessive glutamate) leads to increased release of GABA and to inhibition of GPi and SNr. Together, alterations in direct and indirect pathways in early HD induce inhibition of GPi and SNr GABA neurons and to a decreased release of GABA in their output structure, the thalamus. Disinhibition of the thalamus is responsible for abnormal movements. In late HD (right), corticostriatal and nigrostriatal inputs progressively degenerate, leading to decreased striatal glutamate and DA release. Low striatal glutamate and DA levels trigger dysfunction of both direct and indirect pathway MSNs. Imbalance between the direct and indirect pathways induces hyperkinesia and hypokinesia via two pathways: (1) Alterations in the indirect pathway are similar to early HD and lead to hyperkinetic movements. (3) Dysfunction/degeneration of direct pathway MSNs induces decreased release of GABA and disinhibition of GPi and SNr. Increased activity in GPi and SNr leads to inhibition of the thalamus and hypokinesia. Depending on the stage of dysfunction of direct and indirect pathway MSNs, activity in the basal ganglia could result in hypokinesia or hyperkinesia and would explain why some symptomatic patients display both chorea and akinesia. Enk = enkephalin; GLUT = glutamate; GPe = external segment of the globus pallidus; GPi = internal segment of the globus pallidus; SNc = substantia nigra pars compacta; SNr = substantia nigra pars reticulata; STN = subthalamic nucleus.