Winkler Daniela, Daher Fernanda, Wüstefeld Liane, Hammerschmidt Kurt, Poggi Giulia, Seelbach Anna, Krueger-Burg Dilja, Vafadari Behnam, Ronnenberg Anja, Liu Yanling, Kaczmarek Leszek, Schlüter Oliver M, Ehrenreich Hannelore, Dere Ekrem
Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Germany; DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.
Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Germany; Laboratory of Neurosciences, Federal University of Sao Carlos, Brazil.
Behav Brain Res. 2018 Oct 15;352:35-45. doi: 10.1016/j.bbr.2017.02.011. Epub 2017 Feb 9.
The postsynaptic density proteins 95 (PSD95) and 93 (PSD93) belong to a family of scaffolding proteins, the membrane-associated guanylate kinases (MAGUKs), which are highly enriched in synapses and responsible for organizing the numerous protein complexes required for synaptic development and plasticity. Genetic studies have associated MAGUKs with diseases like autism and schizophrenia, but knockout mice show severe, complex defects with difficult-to-interpret behavioral abnormalities due to major motor dysfunction which is atypical for psychiatric phenotypes. Therefore, rather than studying loss-of-function mutants, we comprehensively investigated the behavioral consequences of reduced PSD95 expression, using heterozygous PSD95 knockout mice (PSD95). Specifically, we asked whether heterozygous PSD95 deficient mice would exhibit alterations in the processing of social stimuli and social behavior. Additionally, we investigated whether PSD95 and PSD93 would reveal any indication of functional or biological redundancy. Therefore, homozygous and heterozygous PSD93 deficient mice were examined in a similar behavioral battery as PSD95 mutants. We found robust hypersocial behavior in the dyadic interaction test in both PSD95 males and females. Additionally, male PSD95 mice exhibited higher levels of aggression and territoriality, while female PSD95 mice showed increased vocalization upon exposure to an anesthetized female mouse. Both male and female PSD95 mice revealed mild hypoactivity in the open field but no obvious motor deficit. Regarding PSD93 mutants, homozygous (but not heterozygous) knockout mice displayed prominent hypersocial behavior comparable to that observed in PSD95 mice, despite a more severe motor phenotype, which precluded several behavioral tests or their interpretation. Considering that PSD95 and PSD93 reduction provoke strikingly similar behavioral consequences, we explored a potential substitution effect and found increased PSD93 protein expression in hippocampal synaptic enrichment preparations of PSD95 mice. These data suggest that both PSD95 and PSD93 are involved in processing of social stimuli and control of social behavior. This important role may be partly assured by functional/behavioral and biological/biochemical redundancy.
突触后致密蛋白95（PSD95）和93（PSD93）属于支架蛋白家族，即膜相关鸟苷酸激酶（MAGUKs），它们在突触中高度富集，负责组织突触发育和可塑性所需的众多蛋白质复合物。遗传学研究已将MAGUKs与自闭症和精神分裂症等疾病联系起来，但基因敲除小鼠表现出严重、复杂的缺陷，由于主要运动功能障碍导致行为异常难以解释，而这在精神疾病表型中并不典型。因此，我们没有研究功能丧失突变体，而是使用杂合PSD95基因敲除小鼠（PSD95）全面研究了PSD95表达降低的行为后果。具体而言，我们询问杂合PSD95缺陷小鼠是否会在社会刺激处理和社会行为方面表现出改变。此外，我们研究了PSD95和PSD93是否会显示出功能或生物学冗余的任何迹象。因此，纯合和杂合PSD93缺陷小鼠在与PSD95突变体类似的行为测试中接受检查。我们发现，在二元互动测试中，PSD95雄性和雌性小鼠均表现出强烈的过度社交行为。此外，雄性PSD95小鼠表现出更高水平的攻击性和领地意识，而雌性PSD95小鼠在接触麻醉的雌性小鼠时叫声增加。雄性和雌性PSD95小鼠在旷场实验中均表现出轻度活动减少，但没有明显的运动缺陷。关于PSD93突变体，纯合（而非杂合）基因敲除小鼠表现出与PSD95小鼠中观察到的类似的显著过度社交行为，尽管其运动表型更严重，但排除了一些行为测试或对其的解释。考虑到PSD95和PSD93减少会引发惊人相似的行为后果，我们探索了一种潜在的替代效应，发现在PSD95小鼠的海马突触富集制剂中PSD93蛋白表达增加。这些数据表明，PSD95和PSD93都参与社会刺激的处理和社会行为的控制。这一重要作用可能部分通过功能/行为和生物学/生化冗余来保证。
