Elucidating the cause of depression in Huntington's disease: Effects of reducing mutant huntingtin protein production in the hippocampus on neurogenesis

Megan Biggi, University of Portland

Copyright for this work is retained by the author.

Abstract

Huntington’s disease is an autosomal-dominant disease characterized by deterioration in motor, cognitive, and emotional function. The majority of research has focused primarily on the motor symptoms associated with Huntington’s disease. However, more recent findings show that many Huntington’s patients develop psychological symptoms, such as depression, a decade before they experience motor symptoms or are aware that they have the fatal neurodegenerative disease. Using a Huntington’s disease transgenic mouse model, we explored the hypothesis that the hippocampus plays a role in depression that manifests in Huntington’s patients before the diagnosis and motor dysfunction. Clinical research suggests that people with depression have significantly decreased levels of neurogenesis in the dentate gyrus of the hippocampus. Here we use an experimental technique known as RNA interference (RNAi) to decrease the amount of toxic mutant huntingtin protein (mHtt) in transgenic Huntington’s mice. Due to the knockdown of mHtt, we hypothesized that the RNAi treatment would make the hippocampus more hospitable to cell division and cell survival. Therefore, the rate of neurogenesis would improve in the dentate gyrus of the hippocampus. In addition, if neurogenesis is involved in depressive-like symptoms, we predicted that we would see a decrease in depressive-like behavior. Using stereotaxic surgical techniques, RNAi gene constructs encapsulated in adeno-associated viral capsids (AAV 2.4) were injected directly bilaterally into the brain, targeting the dentate gyri of transgenic huntingtin mice. The RNAi constructs were allowed to express RNAi over a 12-week period in which a variety of behaviors were evaluated. Following behavioral testing, brain tissue was examined for cellular changes using immunohistochemistry techniques to visualize Doublecortin (DCX), a protein involved in neuronal migration. Animals treated with RNAi exhibited a small, but significant, improvement in the hole board memory task as compared to 3 control animals. Additionally, analysis of immunochemical staining for DCX indicated a significant decrease in the number of DCX positive cells found in the RNAi-mHtt hippocampal tissue. In short, the results suggest that RNAi treatment of the dentate gyrus can elicit subtle changes in memory and hippocampal neurogenesis in transgenic mice expressing the human mutant huntingtin gene.