Pohl Tobias T, Hörnberg Hanna
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Straße 10, Berlin 13125, Germany.
Neuronal Signal. 2022 May 10;6(2):NS20210030. doi: 10.1042/NS20210030. eCollection 2022 Jun.
Neurodevelopmental conditions (or neurodevelopmental disorders, NDDs) are highly heterogeneous with overlapping characteristics and shared genetic etiology. The large symptom variability and etiological heterogeneity have made it challenging to understand the biological mechanisms underpinning NDDs. To accommodate this individual variability, one approach is to move away from diagnostic criteria and focus on distinct dimensions with relevance to multiple NDDs. This domain approach is well suited to preclinical research, where genetically modified animal models can be used to link genetic variability to neurobiological mechanisms and behavioral traits. Genetic factors associated with NDDs can be grouped functionally into common biological pathways, with one prominent functional group being genes associated with the synapse. These include the neuroligins (Nlgns), a family of postsynaptic transmembrane proteins that are key modulators of synaptic function. Here, we review how research using Nlgn mouse models has provided insight into how synaptic proteins contribute to behavioral traits associated with NDDs. We focus on how mutations in different Nlgns affect social behaviors, as differences in social interaction and communication are a common feature of most NDDs. Importantly, mice carrying distinct mutations in Nlgns share some neurobiological and behavioral phenotypes with other synaptic gene mutations. Comparing the functional implications of mutations in multiple synaptic proteins is a first step towards identifying convergent neurobiological pathways in multiple brain regions and circuits.
神经发育病症（或神经发育障碍，NDDs）具有高度异质性，特征重叠且遗传病因相同。巨大的症状变异性和病因异质性使得理解NDDs背后的生物学机制具有挑战性。为了适应这种个体变异性，一种方法是摆脱诊断标准，专注于与多种NDDs相关的不同维度。这种领域方法非常适合临床前研究，在该研究中，可以使用基因改造的动物模型将遗传变异性与神经生物学机制和行为特征联系起来。与NDDs相关的遗传因素可以在功能上分为常见的生物学途径，其中一个突出的功能组是与突触相关的基因。这些包括神经连接蛋白（Nlgns），这是一类突触后跨膜蛋白家族，是突触功能的关键调节因子。在这里，我们回顾了使用Nlgn小鼠模型的研究如何深入了解突触蛋白如何影响与NDDs相关的行为特征。我们关注不同Nlgns中的突变如何影响社交行为，因为社交互动和沟通的差异是大多数NDDs的共同特征。重要的是，携带Nlgns中不同突变的小鼠与其他突触基因突变具有一些神经生物学和行为表型。比较多种突触蛋白中突变的功能影响是识别多个脑区和神经回路中趋同神经生物学途径的第一步。
