Progressive Changes in MOR1 in the Striatum of the Heterozygous Q175 Knock-in Mouse Model of Huntington's Disease

Abstract

Huntington’s disease (HD) is a progressive autosomal dominant neurodegenerative disease that produces pronounced neurodegeneration of neostriatal neurons as well as cortical neurons in HD patients. Despite the fact that HD is caused by a dominant mutation in a single gene, the HTT gene, HD patients display great phenotypic variability related to both motor and mood symptoms. In the early stages of HD, there is a massive preferential loss of medium spiny neurons and asymmetry in the degeneration of the striatal compartments, particularly in the striosomal system (Thu et al., 2010). However, the role of striosomes in relation to HD mouse models still has yet to be elucidated. This study investigates whether the striosome system in the striatum is disrupted in a mouse model of Huntington’s disease (HD), the Q175 HD mouse model. In the human brain, the most striking neuropathology is the significant loss of the medium spiny neurons (MSNs) in the striatum and cortical pyramidal neurons, relative to the neuronal loss in other regions. Post-mortem tissue analysis in both human and animal models of HD, show that the striosome and matrix striatal compartments degenerate in an asymmetrical manner. Could the striosomes be a direct player to the dysfunctions that occur in HD? Furthermore, the striosome neurons are rich in mu-opioid receptors, which are involved in regulating dopamine functions in the brain. Could the disruption of the striosome system explain the changes occurring in the dopamine system in HD? I explored these questions by examining the immunohistochemical and immunofluorescence staining patterns and distributions of mu-opioid receptor 1 (MOR1) in transverse brain sections of the Q175 HD model mice. The initial results suggest an augmentation of the MOR1, a possible upregulation of the receptor, indicating a dysregulation of the striosome-enriched receptor protein. Post-mortem analysis of HD brains has shown that individuals with preferential degeneration of striosomes were more likely to have experienced predominant mood symptoms. These imbalances in the striosome system could contribute to the range of emotional and cognitive problems experienced by HD patients.