Striosomes and mood dysfunction in Huntington's disease

Abstract

Variable phenotype is common in neurological disorders with single-gene inheritance patterns. In Huntington's disease, mood and cognitive symptoms are variably co-expressed with motor symptoms. There is also variable degeneration of neurons in the two major neurochemical compartments of the striatum, the striosomes and the extrastriosomal matrix. To determine whether the phenotypic variability in Huntington's disease is related to this compartmental organization, we carried out a double-blind study in which we used GABA(A) receptor immunohistochemistry to analyse the status of striosomes and matrix in the brains of 35 Huntington's disease cases and 13 control cases, and collected detailed data on the clinical symptomatology expressed by the patients from family members and records. We report here a significant association between pronounced mood dysfunction in Huntington's disease patients and differential loss of the GABA(A) receptor marker in striosomes of the striatum. This association held for both clinical onset and end-stage assessments of symptoms. The cases with accentuated striosome abnormality further exhibited later onset age, lower disease grade and lower CAG repeat length in the HD gene. We found no independent association, however, between CAG repeat length or age of onset and mood dysfunction. We suggest that variation in clinical symptomatology in Huntington's disease is associated with variation in the relative abnormality of GABA(A) receptor expression in the striosome and matrix compartments of the striatum, and that striosome-related circuits may modulate mood functioning.

Temporal regulation of ephrin/Eph signalling is required for the spatial patterning of the mammalian striatum

“…Neurons from striosome and matrix compartments display differential activity during natural behaviour or following psychomotor stimulant treatments (Brown et al, 2002;Canales and Graybiel, 2000). Similarly, the specific loss of neurons from either compartment has been correlated with distinct clinical features in Huntington's disease (Tippett et al, 2007), while selective impairment of the function of either neuronal compartment can have different effects on motor function and behaviour (Tappe and Kuner, 2006).…”

Dysregulation of CalDAG-GEFI and CalDAG-GEFII predicts the severity of motor side-effects induced by anti-parkinsonian therapy

“…The dysfunction of striatal matrix neurons is especially severe for the indirect pathway neurons of the striatum, which in the sensorimotor striatum receive powerful inputs from the motor cortex (4)(5)(6). In different models of parkinsonian states, the gradients and compartmental expression of dopaminergic deficits vary (7)(8)(9), but it seems likely that dysfunctional dopaminergic modulation of corticostriatal motor pathways leading through the matrix compartment is a major contributor to the motor symptoms of Parkinson's disease, and that in a range of movement disorders, compartmentally selective striatal dysfunction is present (10)(11)(12)(13)(14)(15)(16)(17).…”

Computational Investigations of Cognitive Impairment in Huntington's Disease

“…Tippett et al (2007) observed that both directions of progression occur and that the heterogenic pattern is associated with the heterogeneity in clinical symptoms. Interestingly, the balance between striosomal and matrix loss was associated with the number of CAG repeats.…”

“…The direction of neuropathology, from striosomal to matrix or the reverse, was shown to be correlated with mood changes (Tippett, et al, 2007). It is assumed that the dysfunctional striosomal STR-SNc loop underlies this pattern and involves the reinforcement learning system.…”