Milanick William, Li Jianing, Thomas Connon I, Al-Yaari Mohammed, Guerrero-Given Debbie, Kamasawa Naomi, Young Samuel M
Gene Therapy Center, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599, USA; Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, IA 52242, USA.
Gene Therapy Center, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599, USA.
Neuron. 2025 Jun 18;113(12):1886-1897.e9. doi: 10.1016/j.neuron.2025.04.013. Epub 2025 May 13.
The αδs are a family of extracellular synaptic molecules that are auxiliary subunits of voltage-gated Ca channel (Ca) complexes. They are linked to brain disorders and are drug targets. The αδs are implicated in controlling synapse development and function through distinct Ca-dependent and Ca-independent pathways. However, the mechanisms of action remain enigmatic since synapses contain mixtures of αδ isoforms in the pre- and postsynaptic compartments. We developed a triple conditional knockout mouse model and demonstrated the combined selective presynaptic ablation of αδs in vivo in a developing mammalian glutamatergic synapse. We identified presynaptic αδs as positive regulators of Munc13-1 levels, an essential neurotransmitter release protein. We found that mammalian synapse development, presynaptic Ca2.1 organization, and the transsynaptic alignment of presynaptic release sites and postsynaptic glutamate receptors are independent of presynaptic αδs. Therefore, our results define presynaptic αδ regulatory roles and suggest a new αδ role in controlling synaptic strength and plasticity.
αδ 蛋白是一类细胞外突触分子，是电压门控钙通道（Ca）复合体的辅助亚基。它们与脑部疾病有关，是药物靶点。αδ 蛋白通过不同的钙依赖和钙非依赖途径参与控制突触的发育和功能。然而，由于突触在突触前和突触后区室中含有多种 αδ 亚型的混合物，其作用机制仍然不明。我们构建了一种三重条件性敲除小鼠模型，并在发育中的哺乳动物谷氨酸能突触中体内证明了 αδ 蛋白的联合选择性突触前消融。我们确定突触前的 αδ 蛋白是 Munc13-1 水平的正向调节因子，Munc13-1 是一种重要的神经递质释放蛋白。我们发现哺乳动物突触的发育、突触前 Ca2.1 的组织以及突触前释放位点与突触后谷氨酸受体的跨突触排列与突触前的 αδ 蛋白无关。因此，我们的结果确定了突触前 αδ 蛋白的调节作用，并提示了其在控制突触强度和可塑性方面的新作用。
