Brain Institute, Vanderbilt University, Nashville, TN 37240-7933, USA; Department of Pharmacology, Vanderbilt University, 7130A MRB III 465 21st Avenue South, Nashville, TN 37240-7933, USA.
Brain Institute, Vanderbilt University, Nashville, TN 37240-7933, USA; Department of Pharmacology, Vanderbilt University, 7130A MRB III 465 21st Avenue South, Nashville, TN 37240-7933, USA.
Cell Rep. 2023 Feb 28;42(2):112042. doi: 10.1016/j.celrep.2023.112042. Epub 2023 Jan 25.
Rapid release of neurotransmitters in synchrony with action potentials is considered a key hardwired property of synapses. Here, in glutamatergic synapses formed between induced human neurons, we show that action potential-dependent neurotransmitter release becomes progressively desynchronized as synapses mature and age. In this solely excitatory network, the emergence of NMDAR-mediated transmission elicits endoplasmic reticulum (ER) stress leading to downregulation of key presynaptic molecules, synaptotagmin-1 and cysteine string protein α, that synchronize neurotransmitter release. The emergence of asynchronous release with neuronal maturity and subsequent aging is maintained by the high-affinity Ca sensor synaptotagmin-7 and suppressed by the introduction of GABAergic transmission into the network, inhibition of NMDARs, and ER stress. These results suggest that long-term disruption of excitation-inhibition balance affects the synchrony of excitatory neurotransmission in human synapses.
神经递质与动作电位的同步快速释放被认为是突触的一个关键固有特性。在这里，在诱导的人类神经元之间形成的谷氨酸能突触中，我们表明，随着突触的成熟和老化，动作电位依赖性神经递质释放变得越来越不同步。在这个仅由兴奋性神经元组成的网络中，NMDAR 介导的传递的出现会引发内质网 (ER) 应激，导致关键的突触前分子（突触结合蛋白-1 和半胱氨酸-string 蛋白-α）下调，从而使神经递质释放同步。随着神经元的成熟和随后的衰老，异步释放的出现是由高亲和力 Ca 传感器突触结合蛋白-7 维持的，并受到 GABA 能传递、NMDAR 抑制和 ER 应激的抑制。这些结果表明，长期兴奋-抑制平衡的破坏会影响人类突触中兴奋性神经递质的同步性。
