Biochemistry & Molecular Biology, Colorado State University, Fort Collins, CO, USA.
Biological Sciences, State University of New York at Buffalo, Buffalo, NY, USA.
Nat Commun. 2022 Jun 1;13(1):3060. doi: 10.1038/s41467-022-30756-z.
A vital question in neuroscience is how neurons align their postsynaptic structures with presynaptic release sites. Although synaptic adhesion proteins are known to contribute in this process, the role of neurotransmitters remains unclear. Here we inquire whether de novo biosynthesis and vesicular release of a noncanonical transmitter can facilitate the assembly of its corresponding postsynapses. We demonstrate that, in both stem cell-derived human neurons as well as in vivo mouse neurons of purely glutamatergic identity, ectopic expression of GABA-synthesis enzymes and vesicular transporters is sufficient to both produce GABA from ambient glutamate and transmit it from presynaptic terminals. This enables efficient accumulation and consistent activation of postsynaptic GABA receptors, and generates fully functional GABAergic synapses that operate in parallel but independently of their glutamatergic counterparts. These findings suggest that presynaptic release of a neurotransmitter itself can signal the organization of relevant postsynaptic apparatus, which could be directly modified to reprogram the synapse identity of neurons.
神经科学中的一个重要问题是神经元如何将其突触后结构与突触前释放位点对齐。尽管已知突触粘附蛋白在这个过程中起作用，但神经递质的作用仍不清楚。在这里，我们探讨了新合成的非经典递质的囊泡释放是否可以促进其相应突触后结构的组装。我们证明，在干细胞衍生的人类神经元以及纯谷氨酸能身份的体内小鼠神经元中，GABA 合成酶和囊泡转运体的异位表达足以从周围的谷氨酸中产生 GABA 并从突触前末端传递它。这使得突触后 GABA 受体能够有效积累和持续激活，并产生完全功能的 GABA 能突触，它们可以平行但独立于其谷氨酸能对应物运行。这些发现表明，神经递质的突触前释放本身可以发出相关突触后装置的组织信号，这可以直接进行修饰以重新编程神经元的突触特性。
