Department of Cellular and Molecular Physiology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Nat Commun. 2023 Aug 17;14(1):4976. doi: 10.1038/s41467-023-40526-0.
Synaptic adhesion molecules (SAMs) shape the structural and functional properties of synapses and thereby control the information processing power of neural circuits. SAMs are broadly expressed in the brain, suggesting that they may instruct synapse formation and specification via a combinatorial logic. Here, we generate sextuple conditional knockout mice targeting all members of the two major families of presynaptic SAMs, Neurexins and leukocyte common antigen-related-type receptor phospho-tyrosine phosphatases (LAR-PTPRs), which together account for the majority of known trans-synaptic complexes. Using synapses formed by cerebellar Purkinje cells onto deep cerebellar nuclei as a model system, we confirm that Neurexins and LAR-PTPRs themselves are not essential for synapse assembly. The combinatorial deletion of both neurexins and LAR-PTPRs, however, decreases Purkinje-cell synapses on deep cerebellar nuclei, the major output pathway of cerebellar circuits. Consistent with this finding, combined but not separate deletions of neurexins and LAR-PTPRs impair motor behaviors. Thus, Neurexins and LAR-PTPRs are together required for the assembly of a functional cerebellar circuit.
突触黏附分子（SAMs）塑造了突触的结构和功能特性，从而控制了神经回路的信息处理能力。SAM 在大脑中广泛表达，这表明它们可能通过组合逻辑来指导突触的形成和特化。在这里，我们生成了六重条件性敲除小鼠，靶向所有主要的突触前 SAM 家族成员，包括神经连接素和白细胞共同抗原相关型受体磷酸酪氨酸磷酸酶（LAR-PTPRs），它们共同构成了大多数已知的跨突触复合物。我们使用小脑浦肯野细胞与小脑深部核形成的突触作为模型系统，证实神经连接素和 LAR-PTPRs 本身对于突触形成并不是必需的。然而，神经连接素和 LAR-PTPRs 的组合缺失会减少小脑深部核的浦肯野细胞突触，这是小脑回路的主要输出途径。与这一发现一致的是，神经连接素和 LAR-PTPRs 的联合缺失而非单独缺失会损害运动行为。因此，神经连接素和 LAR-PTPRs 共同需要组装一个功能性的小脑回路。
