Behavioral and transcriptomic profiling of mice null for Lphn3, a gene implicated in ADHD and addiction.
Behavioral and transcriptomic profiling of mice null for Lphn3, a gene implicated in ADHD and addiction.
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DOI：
10.1002/mgg3.207
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发表时间：
2016-05
影响因子：
2
通讯作者：
Wallis D
中科院分区：
文献类型：
--
作者：
Orsini CA;Setlow B;DeJesus M;Galaviz S;Loesch K;Ioerger T;Wallis D
Latrophilin 3（LPHN 3）基因（最近更名为Adhesion G蛋白偶联受体L3（ADGRL 3））与注意力缺陷/多动障碍（ADHD）的易感性和成瘾的脆弱性有关。然而，它的作用和功能还没有得到很好的理解，因为没有已知的功能变体。为了表征这种鲜为人知的基因的功能，我们对Lphn 3缺失小鼠进行了表型分析。我们通过工具性反应任务评估了食物奖励和工作记忆的动机，通过旋转棒评估了运动协调，通过强迫游泳评估了抑郁样行为。我们还测量了原代海马和皮质神经元培养的神经突生长。进行标准血液化学和血细胞计数。最后，我们还评估了几个大脑区域的转录组。在行为上，Lphn 3的缺失增加了奖励动机和活动水平。与野生型小鼠相比，Lphn 3缺失小鼠显示出对食物的显著更大的仪器响应，特别是在高响应比率下，并且在强迫游泳测定期间不间断地游泳。然而，Lphn 3的丢失不会干扰工作记忆或运动协调。原代海马和皮质神经元培养表明，空神经元显示相对增强的轴突生长后，在体外2和3天。标准的血液化学小组显示，空有低血清钙水平。最后，对不同发育时间点的前额叶皮质、纹状体和海马组织的转录组的分析表明，Lphn 3的缺失导致基因型依赖性差异基因表达（DGE），特别是细胞粘附分子和钙信号蛋白。大部分DGE随年龄增长而减弱，这与ADHD与皮质成熟延迟有关的观点一致。转录组的变化可能会影响神经元的结构和功能，导致与ADHD和成瘾表型一致的行为异常。这些数据应进一步激发Lphn 3功能的分析，改变基因表达和钙信号的发育时间，以及它们在发育过程中对神经元结构/功能的影响。
The Latrophilin 3 (LPHN3) gene (recently renamed Adhesion G protein‐coupled receptor L3 (ADGRL3)) has been linked to susceptibility to attention deficit/hyperactivity disorder (ADHD) and vulnerability to addiction. However, its role and function are not well understood as there are no known functional variants. To characterize the function of this little known gene, we phenotyped Lphn3 null mice. We assessed motivation for food reward and working memory via instrumental responding tasks, motor coordination via rotarod, and depressive‐like behavior via forced swim. We also measured neurite outgrowth of primary hippocampal and cortical neuron cultures. Standard blood chemistries and blood counts were performed. Finally, we also evaluated the transcriptome in several brain regions. Behaviorally, loss of Lphn3 increases both reward motivation and activity levels. Lphn3 null mice display significantly greater instrumental responding for food than wild‐type mice, particularly under high response ratios, and swim incessantly during a forced swim assay. However, loss of Lphn3 does not interfere with working memory or motor coordination. Primary hippocampal and cortical neuron cultures demonstrate that null neurons display comparatively enhanced neurite outgrowth after 2 and 3 days in vitro. Standard blood chemistry panels reveal that nulls have low serum calcium levels. Finally, analysis of the transcriptome from prefrontal cortical, striatal, and hippocampal tissue at different developmental time points shows that loss of Lphn3 results in genotype‐dependent differential gene expression (DGE), particularly for cell adhesion molecules and calcium signaling proteins. Much of the DGE is attenuated with age, and is consistent with the idea that ADHD is associated with delayed cortical maturation. Transcriptome changes likely affect neuron structure and function, leading to behavioral anomalies consistent with both ADHD and addiction phenotypes. The data should further motivate analyses of Lphn3 function in the developmental timing of altered gene expression and calcium signaling, and their effects on neuronal structure/function during development.