Interneuron Cell Loss in the Human Cerebral Cortex in Huntington’s Disease

Abstract

Huntington’s disease (HD) is characterised by variable symptoms (choreiform movements, cognitive, mood and neuropsychological change) and variable neuropathology in the basal ganglia and the cerebral cortex. Our recent studies have shown that the phenotypic variability in HD is associated with the variable pattern of pyramidal cell loss in the cerebral cortex (Thu et al., 2010). We are now extending these studies to the cortical GABAergic interneurons to determine whether the symptom variation in HD is also associated with the variable pattern of interneuron cell loss in the cerebral cortex. The GABAergic interneurons in the cortex are inhibitory neurons that act locally to modulate the activity of pyramidal neurons, hence are critical determinants of cortical output. To undertake this study, unbiased stereological cell counting methods were used to quantify three major types of GABAergic interneurons immunoreactive for calbindin-D28k, calretinin, and parvalbumin in the primary motor and anterior cingulate cortices in 13 HD and 14 matched control cases of the post-mortem human brain. The HD cases were categorised into 3 dominant symptom groups (“motor”, “mood”, or “mixed” groups). Detailed data on the symptomatology of HD cases was collected from family members and clinical records as previously described (Tippett et al., 2007; Thu, et al., 2010). The results demonstrated a heterogeneous loss of interneurons across the two cortical regions in HD cases compared to control cases. Most interestingly, the major findings of the present study showed a significant association between the pattern of cortical interneuron cell loss and the variable symptomatology in HD. The results showed that in the anterior cingulate cortex, there was a major significant interneuron loss in all three interneuronal populations (71% loss of calbindin-D28k+, 60% loss of calretinin+, 80% loss of parvalbumin+ interneurons) in HD cases with major “mood” disorder, but no significant interneuron loss was observed in the cingulate cortex in the HD cases with major “motor” symptoms. By contrast, in the primary motor cortex, there was a selective loss of calbindin-D28k+ interneurons (57% loss) in HD cases with major “motor” symptoms, but no significant interneuron loss was observed in the motor cortex in cases with a dominant mood phenotype. These findings show that there is a major heterogeneous pattern of interneuron loss in the cerebral cortex which correlates with symptom variation in HD, which suggests that cortical neurodegeneration is a key component in understanding the neural basis of clinical heterogeneity in HD.