Failure to Thrive: Impaired BDNF Transport along the Cortical–Striatal Axis in Mouse Q140 Neurons of Huntington’s Disease

SIMPLE SUMMARY: The brain-derived neurotrophic factor (BDNF) is implicated in the function and survival of striatal neurons. Deficits in neurotrophic support by BDNF have been hypothesized to contribute to the neurodegeneration of striatal neurons in Huntington’s disease (HD). This article outlines an investigation into defects in the transport of BDNF along the cortical–striatal axis in primary neurons isolated from the Q140 mouse model of HD. Herein we employ a microfluidic chamber cell culture system specifically designed to grow cortical–striatal co-cultures. Within this system, we employed quantum dot-conjugated BDNF (QD-BDNF) to visualize single-molecule transport behaviors of BDNF undergoing axonal and dendritic transport. We found a global defect in the supply of QD-BDNF moving anterogradely along cortical axons, and retrogradely within the striatal dendrites of Q140 primary neurons. These findings support the notion that the essential spatiotemporal support from BDNF to striatal neurons is reduced due to deficits in its cortical–striatal transport, a defect contributing to striatal neurodegeneration in HD. BDNF trophic support has been proposed as a therapeutic intervention to delay or prevent the onset and progression of neurodegenerative diseases. Our study provides additional insight into how therapeutic strategies involving BDNF supplementation may be applied for Huntington’s or other diseases. ABSTRACT: Boosting trophic support to striatal neurons by increasing levels of brain-derived neurotrophic factor (BDNF) has been considered as a target for therapeutic intervention for several neurodegenerative diseases, including Huntington’s disease (HD). To aid in the implementation of such a strategy, a thorough understanding of BDNF cortical–striatal transport is critical to help guide its strategic delivery. In this manuscript, we investigate the dynamic behavior of BDNF transport along the cortical–striatal axis in Q140 primary neurons, a mouse model for HD. We examine this by using single-molecule labeling of BDNF conjugated with quantum dots (QD-BDNF) to follow the transport along the cortical–striatal axis in a microfluidic chamber system specifically designed for the co-culture of cortical and striatal primary neurons. Using this approach, we observe a defect of QD-BDNF transport in Q140 neurons. Our study demonstrates that QD-BDNF transport along the cortical–striatal axis involves the impairment of anterograde transport within axons of cortical neurons, and of retrograde transport within dendrites of striatal neurons. One prominent feature we observe is the extended pause time of QD-BDNF retrograde transport within Q140 striatal dendrites. Taken together, these finding support the hypothesis that delinquent spatiotemporal trophic support of BDNF to striatal neurons, driven by impaired transport, may contribute to the pathogenesis of HD, providing us with insight into how a BDNF supplementation therapeutic strategy may best be applied for HD.