ORIGINAL RESEARCH published: 24 December 2018 doi: 10.3389/fnmol.2018.00478 Altered Synaptic Vesicle Release and Ca 2+ Influx at Single Presynaptic Terminals of Cortical Neurons in a Knock-in Mouse Model of Huntington’s Disease Sidong Chen 1† , Chenglong Yu 1† , Li Rong 1 , Chun Hei Li 1 , Xianan Qin 2 , Hoon Ryu 3 and Hyokeun Park 1,2,4 * 1 Division of Life Science, The Hong Kong University of Science and Technology, Kowloon, Hong Kong, 2 Department of Physics, The Hong Kong University of Science and Technology, Kowloon, Hong Kong, 3 Department of Neurology, Boston University School of Medicine, Boston, MA, United States, 4 State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Kowloon, Hong Kong Edited by: Jaichandar (Jai) Subramanian, University of Kansas, United States Reviewed by: Anna Fejtova, Universitätsklinikum Erlangen, Germany Anthony John Hannan, Florey Institute of Neuroscience and Mental Health, Australia *Correspondence: Hyokeun Park hkpark@ust.hk † These authors have contributed equally to this work Received: 12 July 2018 Accepted: 06 December 2018 Published: 24 December 2018 Citation: Chen S, Yu C, Rong L, Li CH, Qin X, Ryu H and Park H (2018) Altered Synaptic Vesicle Release and Ca 2+ Influx at Single Presynaptic Terminals of Cortical Neurons in a Knock-in Mouse Model of Huntington’s Disease. Front. Mol. Neurosci. 11:478. doi: 10.3389/fnmol.2018.00478 Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by the abnormal expansion of CAG repeats in the huntingtin (HTT ) gene, which leads to progressive loss of neurons starting in the striatum and cortex. One possible mechanism for this selective loss of neurons in the early stage of HD is altered neurotransmission at synapses. Despite the recent finding that presynaptic terminals play an important role in HD, neurotransmitter release at synapses in HD remains poorly understood. Here, we measured synaptic vesicle release in real time at single presynaptic terminals during electrical field stimulation. We found the increase in synaptic vesicle release at presynaptic terminals in primary cortical neurons in a knock-in mouse model of HD (zQ175). We also found the increase in Ca 2+ influx at presynaptic terminals in HD neurons during the electrical stimulation. Consistent with increased Ca 2+ -dependent neurotransmission in HD neurons, the increase in vesicle release and Ca 2+ influx was rescued with Ca 2+ chelators or by blocking N-type voltage-gated Ca 2+ channels, suggesting N-type voltage-gated Ca 2+ channels play an important role in HD. Taken together, our results suggest that the increased synaptic vesicles release due to increased Ca 2+ influx at presynaptic terminals in cortical neurons contributes to the selective neurodegeneration of these neurons in early HD and provide a possible therapeutic target. Keywords: Huntington’s disease, synaptic vesicle release, calcium influx, real-time imaging, presynaptic terminal INTRODUCTION Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by an increase in CAG trinucleotide repeats in the huntingtin (HTT) gene, giving rise to an expanded polyglutamine (polyQ) domain in the N-terminal of the encoded HTT protein (MacDonald et al., 1993). The main clinical symptoms of HD include severe involuntary motor dysfunction, psychiatric disturbance, cognitive impairment, and eventual death (Dayalu and Albin, 2015). Although the HTT gene is ubiquitously expressed throughout the human body, the medium spiny Frontiers in Molecular Neuroscience | www.frontiersin.org 1 December 2018 | Volume 11 | Article 478