Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA.
Neuroscience Department, Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
Nat Commun. 2023 Jan 28;14(1):459. doi: 10.1038/s41467-023-36042-w.
Multiple trans-synaptic complexes organize synapse development, yet their roles in the mature brain and cooperation remain unclear. We analyzed the postsynaptic adhesion protein LRRTM1 in the prefrontal cortex (PFC), a region relevant to cognition and disorders. LRRTM1 knockout (KO) mice had fewer synapses, and we asked whether other synapse organizers counteract further loss. This determined that the immunoglobulin family member SynCAM 1 controls synapse number in PFC and was upregulated upon LRRTM1 loss. Combined LRRTM1 and SynCAM 1 deletion substantially lowered dendritic spine number in PFC, but not hippocampus, more than the sum of single KO impairments. Their cooperation extended presynaptically, and puncta of Neurexins, LRRTM1 partners, were less abundant in double KO (DKO) PFC. Electrophysiology and fMRI demonstrated aberrant neuronal activity in DKO mice. Further, DKO mice were impaired in social interactions and cognitive tasks. Our results reveal concerted roles of LRRTM1 and SynCAM 1 across synaptic, network, and behavioral domains.
多个跨突触复合物组织突触发育，但它们在成熟大脑中的作用和协作仍不清楚。我们分析了前额叶皮层（PFC）中突触后粘附蛋白 LRRTM1，该区域与认知和疾病有关。LRRTM1 敲除（KO）小鼠的突触较少，我们想知道是否有其他的突触组织者可以防止进一步的损失。这表明免疫球蛋白家族成员 SynCAM 1 控制着 PFC 中的突触数量，并且在 LRRTM1 缺失时会上调。LRRTM1 和 SynCAM 1 的联合缺失显著降低了 PFC 中的树突棘数量，但在海马体中没有，比单个 KO 损伤的总和还要多。它们的合作延伸到了突触前，并且在 DKO（双敲除）PFC 中，LRRTM1 伴侣 Neurexins 的突触点较少。电生理学和 fMRI 显示 DKO 小鼠的神经元活动异常。此外，DKO 小鼠在社交互动和认知任务中表现受损。我们的结果揭示了 LRRTM1 和 SynCAM 1 在突触、网络和行为领域的协同作用。
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