Neurodegenerative diseases have become one of the major challenges in public health. More people suffer from neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and Huntington’s disease (HD). As these diseases progress, patients have severe symptoms including dementia, memory and learning deficits, cognitive dysfunction, and mental disorders. HD is an autosomal dominant neurodegenerative disease. HD patients suffer from progressive motor dysfunction, cognitive defects and neuropsychiatric dysfunctions, and eventually death. It was revealed that HD is caused by the abnormal expansion of the cytosine-adenine-guanine (CAG) repeat in the huntingtin gene. Many researchers have focused on uncovering the pathogenic mechanisms of HD. However, the detailed mechanisms o...[ Read more ]

Neurodegenerative diseases have become one of the major challenges in public health. More people suffer from neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and Huntington’s disease (HD). As these diseases progress, patients have severe symptoms including dementia, memory and learning deficits, cognitive dysfunction, and mental disorders. HD is an autosomal dominant neurodegenerative disease. HD patients suffer from progressive motor dysfunction, cognitive defects and neuropsychiatric dysfunctions, and eventually death. It was revealed that HD is caused by the abnormal expansion of the cytosine-adenine-guanine (CAG) repeat in the huntingtin gene. Many researchers have focused on uncovering the pathogenic mechanisms of HD. However, the detailed mechanisms of neurodegeneration in HD remain elusive. In particular, how synaptic transmission is altered in the early stage of HD is not clearly understood yet. Here, I investigated synaptic vesicles release during electrical stimulation in single presynaptic terminals level in cultured cortical neurons of a zQ175KI HD mouse model (zQ175) and found that the release of synaptic vesicles is altered during stimulation in HD cortical neurons. Furthermore, the Ca²⁺ influx during electrical stimulation significantly increased during stimulation in cultured neurons of HD mice. Intriguingly, this increase was prevented by treating with either BAPTA-AM or ω-conotoxin GVIA (N-type VGCC blocker), suggesting the involvement of N-type voltage-gated Ca²⁺ channels in HD. To further study altered dynamics and exocytosis of synaptic vesicles, I also performed real-time 3D tracking of single synaptic vesicle in cultured cortical neurons of zQ175 mice. I found abnormal mobility and altered vesicle pools of releasing synaptic vesicles. Overexpressing Rab11 or constitutive active form of Rab11 (EGFP-Rab11AQ70L) rescued the abnormal dynamics and vesicle pools of synaptic vesicles. Taken together, my work provides new insight into synaptic transmission in the early stage of HD and shed new light into a possible therapeutic target for HD.