GABAergic inhibition regulates developmental synapse elimination in the cerebellum

发育过程中功能性神经回路的形成涉及大量冗余突触的消除。在小脑中，兴奋性攀爬纤维（CF）与浦肯野细胞（PC）之间的一对一连接是通过消除早期形成的多余CFs来建立的。这一过程依赖于谷氨酸能兴奋性输入，但gaba能传递的贡献尚不清楚。本研究表明，GABA合成酶GAD67的单个等位基因突变、pc和GABA能中间神经元中GAD67的有条件缺失或小脑GAD活性的药物抑制导致GABA能传递减少的小鼠模型中CF突触消除受损。局部应用地西泮可增强小脑GABAA受体的敏感性，从而挽救CF突触受损的消除。我们的电生理和Ca^<2+>成像数据表明，GABAA受体介导的分子层中间神经元对PC体细胞的抑制影响了CF诱导的体细胞内Ca^<2+>瞬变，并调节了从出生后第10天（P10）到P16左右的CF突触消除。

Functional neural circuit formation during development involves massive elimination of redundant synapses. In the cerebellum, one-to-one connection from excitatory climbing fiber (CF) to Purkinje cell (PC) is established by elimination of early-formed surplus CFs. This process depends on glutamatergic excitatory inputs, but contribution of GABAergic transmission remains unclear. Here we demonstrate impaired CF synapse elimination in mouse models with diminished GABAergic transmission by mutation of a single allele for the GABA synthesizing enzyme GAD67, conditional deletion of GAD67 from PCs and GABAergic interneurons or pharmacological inhibition of cerebellar GAD activity. The impaired CF synapse elimination was rescued by enhancing GABAA receptor sensitivity in the cerebellum by locally applied diazepam. Our electrophysiological and Ca^<2+> imaging data suggest that GABAA receptor-mediated inhibition onto the PC soma from molecular layer interneurons influences CF-induced Ca^<2+> transients in the soma and regulates CF synapse elimination from postnatal day 10 (P10) to around P16.