Neuroscience Graduate Program, University of Cincinnati, United States of America.
Department of Obstetrics and Gynecology, Indiana University School of Medicine, United States of America.
Neurobiol Dis. 2019 Oct;130:104494. doi: 10.1016/j.nbd.2019.104494. Epub 2019 Jun 6.
Attention deficit hyperactivity disorder is a pervasive developmental disorder characterized by inattention, impulsivity, and hyperactivity and is 75-90% heritable. Latrophilin-3 (LPHN3; or ADGRL(3)) is associated with a subtype of ADHD, but how it translates to symptoms is unknown. LPHN3 is a synaptic adhesion G protein coupled receptor that binds to fibronectin leucine rich transmembrane protein 3 and teneurin-3 (FLRT3 and TEN-3). We created a null mutation of Lphn3 (KO) in Sprague-Dawley rats using CRISPR/Cas9 to delete exon-3. The KO rats had no effects on reproduction or survival but reduced growth. KO females showed catch-up weight gain whereas KO males did not. We tested WT and KO littermates for home-cage activity, anxiety-like behavior, acoustic startle response, and activity after amphetamine challenge. Expression of Lphn3-related genes, monoamines, and receptors were determined. Lphn3 KO rats showed persistent hyperactivity, increased acoustic startle, reduced activity in response to amphetamine relative to baseline, and female-specific reduced anxiety-like behavior. Expression of Lphn1, Lphn2, and Flrt3 by qPCR and their protein products by western-blot analysis showed no compensatory upregulation. Striatal tyrosine hydroxylase, aromatic L-amino acid decarboxylase (AADC), and the dopamine transporter were increased and dopamine D1 receptor (DRD1) and dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32) decreased with no changes in DRD2, DRD4, vesicular monoamine transporter-2, N-methyl-d-aspartate (NMDA)-NR1, -NR2A, or -NR2B. LPHN3 is expressed in many brain regions but its function is largely unknown. Data from human, mouse, zebrafish, Drosophila and our new Lphn3 KO rat data collectively show that its disruption is significantly correlated with hyperactivity and associated striatal changes in dopamine markers.
注意缺陷多动障碍是一种普遍存在的发育障碍，其特征为注意力不集中、冲动和多动，其遗传性为 75-90%。Latrophilin-3（LPHN3；或 ADGRL3）与 ADHD 的一个亚型有关，但它如何转化为症状尚不清楚。LPHN3 是一种突触黏附 G 蛋白偶联受体，与纤维连接蛋白富含亮氨酸跨膜蛋白 3 和 teneurin-3（FLRT3 和 TEN-3）结合。我们使用 CRISPR/Cas9 在 Sprague-Dawley 大鼠中创建了 Lphn3（KO）的缺失突变，以删除外显子 3。KO 大鼠对繁殖或存活没有影响，但生长减少。KO 雌性表现出追赶体重增加，而 KO 雄性则没有。我们测试了 WT 和 KO 同窝仔鼠的笼内活动、焦虑样行为、声惊反射和安非他命挑战后的活动。确定了 Lphn3 相关基因、单胺类和受体的表达。与 WT 相比，Lphn3 KO 大鼠表现出持续的多动、增加的声惊反射、对安非他命的反应性降低以及女性特异性焦虑样行为减少。通过 qPCR 测定 Lphn1、Lphn2 和 Flrt3 的表达及其蛋白质产物的 Western-blot 分析显示没有代偿性上调。纹状体酪氨酸羟化酶、芳香族 L-氨基酸脱羧酶（AADC）和多巴胺转运体增加，多巴胺 D1 受体（DRD1）和多巴胺和 cAMP 调节神经元磷酸蛋白（DARPP-32）减少，而 DRD2、DRD4、囊泡单胺转运体-2、N-甲基-D-天冬氨酸（NMDA）-NR1、-NR2A 或-NR2B 无变化。LPHN3 在许多脑区表达，但功能尚不清楚。来自人类、小鼠、斑马鱼、果蝇和我们新的 Lphn3 KO 大鼠的数据共同表明，其破坏与多动和相关的纹状体多巴胺标志物变化显著相关。
