Li Xiling, Chien Chun, Han Yifu, Sun Zihan, Chen Xun, Dickman Dion
Department of Neurobiology, University of Southern California, Los Angeles, CA, 90089, USA.
USC Neuroscience Graduate Program, Los Angeles, CA, 90089, USA.
Sci Adv. 2021 Dec 3;7(49):eabj1215. doi: 10.1126/sciadv.abj1215. Epub 2021 Dec 1.
Homeostatic modulation of presynaptic neurotransmitter release is a fundamental form of plasticity that stabilizes neural activity, where presynaptic homeostatic depression (PHD) can adaptively diminish synaptic strength. PHD has been proposed to operate through an autocrine mechanism to homeostatically depress release probability in response to excess glutamate release at the neuromuscular junction. This model implies the existence of a presynaptic glutamate autoreceptor. We systematically screened all neuronal glutamate receptors in the fly genome and identified the glutamate-gated chloride channel (α) to be required for the expression of PHD. Pharmacological, genetic, and Ca imaging experiments demonstrate that GluClα acts locally at axonal terminals to drive PHD. Unexpectedly, GluClα localizes and traffics with synaptic vesicles to drive presynaptic inhibition through an activity-dependent anionic conductance. Thus, GluClα operates as both a sensor and effector of PHD to adaptively depress neurotransmitter release through an elegant autocrine inhibitory signaling mechanism at presynaptic terminals.
突触前神经递质释放的稳态调节是一种稳定神经活动的基本可塑性形式，其中突触前稳态抑制（PHD）可适应性地降低突触强度。有人提出PHD通过自分泌机制起作用，以响应神经肌肉接头处过量的谷氨酸释放，稳态地降低释放概率。该模型意味着存在突触前谷氨酸自身受体。我们系统地筛选了果蝇基因组中的所有神经元谷氨酸受体，并确定谷氨酸门控氯离子通道（α）是PHD表达所必需的。药理学、遗传学和钙成像实验表明，GluClα在轴突末端局部起作用以驱动PHD。出乎意料的是，GluClα与突触小泡一起定位和运输，通过依赖于活动的阴离子电导来驱动突触前抑制。因此，GluClα作为PHD的传感器和效应器，通过突触前末端一种精巧的自分泌抑制信号机制，适应性地降低神经递质释放。
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