Abstract
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 Ca2+ influx at presynaptic terminals in HD neurons during the electrical stimulation. Consistent with increased Ca2+-dependent neurotransmission in HD neurons, the increase in vesicle release and Ca2+ influx was rescued with Ca2+ chelators or by blocking N-type voltage-gated Ca2+ channels, suggesting N-type voltage-gated Ca2+ channels play an important role in HD. Taken together, our results suggest that the increased synaptic vesicles release due to increased Ca2+ influx at presynaptic terminals in cortical neurons contributes to the selective neurodegeneration of these neurons in early HD and provide a possible therapeutic target.
Highlights
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 domain in the N-terminal of the encoded HTT protein (MacDonald et al, 1993)
To examine whether synaptic transmission is altered at single presynaptic terminals in HD neurons, we measured the release of synaptic vesicles at single presynaptic terminals in dissociated cortical neurons cultured from zQ175 mice, a recently developed knock-in mouse model of HD that is more relevant to human HD than other models in terms of genetic context and recapitulating the late onset, slow natural progression, and neuropathology of HD patients
We measured the relative proportion of excitatory neurons in dissociated cortical neurons by plating low-density WT and HD cortical neurons isolated from postnatal day 0 (P0) littermates; the neurons were cultured until mature, functional synapses were formed
Summary
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). Increased activity of extrasynaptic N-methyl-D-aspartate receptors (NMDARs) was suggested to lead to the degeneration of striatal neurons (Milnerwood et al, 2010; Botelho et al, 2014; Plotkin et al, 2014). Activation of the NMDAR can be induced by the release of neurotransmitters from presynaptic terminals (Blanton et al, 1990; Atasoy et al, 2008). In this respect, it is interesting to note that mutant HTT protein has been reported to alter the exocytosis of presynaptic vesicles (DiFiglia et al, 1995; Morton et al, 2001; Romero et al, 2008; Joshi et al, 2009). The release of neurotransmitters at single presynaptic terminals as an input of corticostriatal synapses in HD remains poorly understood
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