University of Zurich, Institute of Pharmacology and Toxicology, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
University Claude Bernard Lyon 1, CNRS UMR 5284, INSERM U 1314, Melis, 69008 Lyon, France.
Cell Rep. 2023 Aug 29;42(8):112947. doi: 10.1016/j.celrep.2023.112947. Epub 2023 Aug 10.
The molecular code that controls synapse formation and maintenance in vivo has remained quite sparse. Here, we identify that the secreted protein Adamtsl3 functions as critical hippocampal synapse organizer acting through the transmembrane receptor DCC (deleted in colorectal cancer). Traditionally, DCC function has been associated with glutamatergic synaptogenesis and plasticity in response to Netrin-1 signaling. We demonstrate that early post-natal deletion of Adamtsl3 in neurons impairs DCC protein expression, causing reduced density of both glutamatergic and GABAergic synapses. Adult deletion of Adamtsl3 in either GABAergic or glutamatergic neurons does not interfere with DCC-Netrin-1 function at glutamatergic synapses but controls DCC signaling at GABAergic synapses. The Adamtsl3-DCC signaling unit is further essential for activity-dependent adaptations at GABAergic synapses, involving DCC phosphorylation and Src kinase activation. These findings might be particularly relevant for schizophrenia because genetic variants in Adamtsl3 and DCC have been independently linked with schizophrenia in patients.
控制体内突触形成和维持的分子密码仍然相当稀少。在这里，我们发现分泌蛋白 Adamtsl3 通过跨膜受体 DCC（结直肠癌缺失）作为关键的海马突触组织者发挥作用。传统上，DCC 的功能与谷氨酸能突触发生和对 Netrin-1 信号的可塑性有关。我们证明，神经元中 Adamtsl3 的早期出生后缺失会损害 DCC 蛋白的表达，导致谷氨酸能和 GABA 能突触的密度降低。成年后 GABA 能或谷氨酸能神经元中 Adamtsl3 的缺失不会干扰谷氨酸能突触处的 DCC-Netrin-1 功能，但会控制 GABA 能突触处的 DCC 信号。Adamtsl3-DCC 信号单元对于 GABA 能突触的活性依赖性适应也是必不可少的，涉及 DCC 磷酸化和Src 激酶的激活。这些发现可能与精神分裂症特别相关，因为 Adamtsl3 和 DCC 的遗传变异已被独立地与患者中的精神分裂症相关联。
