Decreased BDNF Release in Cortical Neurons of a Knock-in Mouse Model of Huntington\u2019s Disease

Chenglong Yu,Hyokeun Park,Hanna Yoo,Sidong Chen,Xianan Qin,Chun Hei Li

doi:10.1038/s41598-018-34883-w

Chenglong Yu, Hyokeun Park + Show 4 more

Open Access

https://doi.org/10.1038/s41598-018-34883-w

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Abstract

Huntington’s disease (HD) is a dominantly inherited neurodegenerative disease caused by an increase in CAG repeats in the Huntingtin gene (HTT). The striatum is one of the most vulnerable brain regions in HD, and altered delivery of BDNF to the striatum is believed to underlie this high vulnerability. However, the delivery of BDNF to the striatum in HD remains poorly understood. Here, we used real-time imaging to visualize release of BDNF from cortical neurons cultured alone or co-cultured with striatal neurons. BDNF release was significantly decreased in the cortical neurons of zQ175 mice (a knock-in model of HD), and total internal reflection fluorescence microscopy revealed several release patterns of single BDNF-containing vesicles, with distinct kinetics and prevalence, in co-cultured cortical HD neurons. Notably, a smaller proportion of single BDNF-containing vesicles underwent full release in HD neurons than in wild-type neurons. This decreased release of BDNF in cortical neurons might lead to decreased BDNF levels in the striatum because the striatum receives BDNF mainly from the cortex. In addition, we observed a decrease in the total travel length and speed of BDNF-containing vesicles in HD neurons, indicating altered transport of these vesicles in HD. Our findings suggest a potential mechanism for the vulnerability of striatal neurons in HD and offer new insights into the pathogenic mechanisms underlying the degeneration of neurons in HD.

Highlights

Huntington’s disease (HD), a dominantly inherited neurodegenerative disease, is caused by an expansion of CAG repeats in the Huntingtin gene (HTT)[1,2]
We found a significant decrease in secreted brain-derived neurotrophic factor (BDNF) levels in HD cortical neurons compared to WT neurons (p = 0.0065, Mann-Whitney U test, Supplementary Fig. S1)
The release ratio of BDNF-pHluorin during stimulation was calculated as the intensity ratio [I1/(I1 + I2)] (Fig. 1E) in order to reflect the variance in fluorescent puncta; the results show that the release ratio during stimulation was significantly lower in HD neurons than WT neurons (p = 0.0000003892, Mann-Whitney U test, Fig. 1E)

Summary

Introduction

Huntington’s disease (HD), a dominantly inherited neurodegenerative disease, is caused by an expansion of CAG repeats in the Huntingtin gene (HTT)[1,2] This CAG-repeat expansion in the gene results in an increased polyglutamine stretch in the translated mutant huntingtin protein, which plays a detrimental role in neurons[3,4,5]. Studies using HD mouse models found that BDNF levels were diminished in both cortical and striatal neurons[23,24], which agrees with the findings of studies regarding the striatum in HD patients[25]. Our results suggest that altered release and transport of BDNF-containing vesicles contributes to the impaired delivery of BDNF to the striatum in HD, thereby increasing the vulnerability of these neurons

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