Department of Molecular Neuroscience, Faculty of Medicine, University of Toyama, Toyama, 930-0194, Japan.
Research Center for Idling Brain Science, University of Toyama, Toyama, 930-0194, Japan.
Mol Brain. 2024 Mar 12;17(1):16. doi: 10.1186/s13041-024-01087-5.
Neuroligin (NLGN) 3 is a postsynaptic cell adhesion protein organizing synapse formation through two different types of transsynaptic interactions, canonical interaction with neurexins (NRXNs) and a recently identified noncanonical interaction with protein tyrosine phosphatase (PTP) δ. Although, NLGN3 gene is known as a risk gene for neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability (ID), the pathogenic contribution of the canonical NLGN3-NRXN and noncanonical NLGN3-PTPδ pathways to these disorders remains elusive. In this study, we utilized Nlgn3 mutant mice selectively lacking the interaction with either NRXNs or PTPδ and investigated their social and memory performance. Neither Nlgn3 mutants showed any social cognitive deficiency in the social novelty recognition test. However, the Nlgn3 mutant mice lacking the PTPδ pathway exhibited significant decline in the social conditioned place preference (sCPP) at the juvenile stage, suggesting the involvement of the NLGN3-PTPδ pathway in the regulation of social motivation and reward. In terms of learning and memory, disrupting the canonical NRXN pathway attenuated contextual fear conditioning while disrupting the noncanonical NLGN3-PTPδ pathway enhanced it. Furthermore, disruption of the NLGN3-PTPδ pathway negatively affected the remote spatial reference memory in the Barnes maze test. These findings highlight the differential contributions of the canonical NLGN3-NRXN and noncanonical NLGN3-PTPδ synaptogenic pathways to the regulation of higher order brain functions associated with ASD and ID.
神经黏连蛋白 3（NLGN3）是一种突触后细胞黏附蛋白，通过两种不同类型的突触间相互作用来组织突触形成，即与神经连接蛋白（NRXNs）的经典相互作用和与蛋白酪氨酸磷酸酶（PTP）δ的最近发现的非经典相互作用。尽管 NLGN3 基因被认为是神经发育障碍（如自闭症谱系障碍（ASD）和智力障碍（ID））的风险基因，但经典的 NLGN3-NRXN 和非经典的 NLGN3-PTPδ 途径对这些疾病的致病贡献仍不清楚。在这项研究中，我们利用选择性缺乏与 NRXNs 或 PTPδ 相互作用的 Nlgn3 突变小鼠，研究了它们的社交和记忆表现。Nlgn3 突变小鼠在社交新颖性识别测试中均未表现出任何社交认知缺陷。然而，缺乏 PTPδ 途径的 Nlgn3 突变小鼠在幼年时表现出社交条件性位置偏好（sCPP）的显著下降，表明 NLGN3-PTPδ 途径参与了社交动机和奖励的调节。在学习和记忆方面，破坏经典的 NRXN 途径会减弱情境性恐惧条件反射，而破坏非经典的 NLGN3-PTPδ 途径则会增强其作用。此外，破坏 NLGN3-PTPδ 途径会对 Barnes 迷宫测试中的远程空间参考记忆产生负面影响。这些发现强调了经典的 NLGN3-NRXN 和非经典的 NLGN3-PTPδ 突触形成途径对与 ASD 和 ID 相关的高级脑功能的调节的不同贡献。
