Sociability Deficits and Altered Amygdala Circuits in Mice Lacking Pcdh10, an Autism Associated Gene.
Sociability Deficits and Altered Amygdala Circuits in Mice Lacking Pcdh10, an Autism Associated Gene.
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DOI：
10.1016/j.biopsych.2016.06.008
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发表时间：
2017-02-01
影响因子：
10.6
通讯作者：
Brodkin, Edward S.
中科院分区：
文献类型：
--
作者：
Schoch, Hannah;Kreibich, Arati S.;Ferri, Sarah L.;White, Rachel S.;Bohorquez, Dominique;Banerjee, Anamika;Port, Russell G.;Dow, Holly C.;Cordero, Lucero;Pallathra, Ashley A.;Kim, Hyong;Li, Hongzhe;Bilker, Warren B.;Hirano, Shinji;Schultz, Robert T.;Borgmann-Winter, Karin;Hahn, Chang-Gyu;Feldmeyer, Dirk;Carlson, Gregory C.;Abel, Ted;Brodkin, Edward S.
自闭症谱系障碍（ASD）患者的行为症状归因于异常的神经元连接，但这些行为和大脑表型的分子基础在很大程度上是未知的。人类遗传学研究表明，原钙粘蛋白10（Protocadherin 10，PCDH 10）是非成簇原钙粘蛋白基因δ2亚家族的成员，与ASD有关。PCDH 10表达在基底外侧杏仁核中富集，这是一个与ASD的社交缺陷有关的脑区。先前的研究表明Pcdh 10在轴突生长和突触消除中发挥作用，但其在社会行为和杏仁核神经元连接中的作用尚不清楚。我们假设Pcdh 10的单倍不足会减少社会接近行为，改变杏仁核回路的结构和功能。评估了缺乏一个拷贝的Pcdh 10（Pcdh 10 +/−）和野生型同窝小鼠（WT）的社交方式和其他行为。外侧/基底外侧杏仁核树突棘的数量和形态进行了评估，杏仁核电路功能进行了研究，使用电压敏感染料成像。Pcdh 10和N-甲基-D-天冬氨酸受体（NMDAR）亚基的表达进行了评估，在突触后密度的杏仁核部分。雄性Pcdh 10 +/−小鼠的社会接近行为减少，γ同步受损，脊柱形态异常，杏仁核中NMDAR亚基水平降低。Pcdh 10 +/−男性的社交途径缺陷通过使用NMDAR部分激动剂d-环丝氨酸进行急性治疗而得以挽救。我们的研究表明，雄性Pcdh 10 +/−小鼠具有突触和行为缺陷，并建立Pcdh 10 +/−小鼠作为研究ASD相关神经回路和行为变化的新型遗传模型。
Behavioral symptoms in individuals with autism spectrum disorder (ASD) have been attributed to abnormal neuronal connectivity, but the molecular bases of these behavioral and brain phenotypes are largely unknown. Human genetic studies have implicated Protocadherin 10 (PCDH10), a member of the δ2 subfamily of non-clustered protocadherin genes, in ASD. PCDH10 expression is enriched in the basolateral amygdala, a brain region implicated in the social deficits of ASD. Previous reports indicate that Pcdh10 plays a role in axon outgrowth and glutamatergic synapse elimination, but its roles in social behaviors and amygdala neuronal connectivity are unknown. We hypothesized that haploinsufficiency of Pcdh10 would reduce social approach behavior and alter the structure and function of amygdala circuits. Mice lacking one copy of Pcdh10 (Pcdh10+/−) and wildtype littermates (WT) were assessed for social approach and other behaviors. The lateral/basolateral amygdala was assessed for dendritic spine number and morphology, and amygdala circuit function was studied using voltage sensitive dye imaging. Expression of Pcdh10 and N-methyl-D-aspartate receptor (NMDAR) subunits was assessed in post-synaptic density fractions of amygdala. Male Pcdh10+/− mice have reduced social approach behavior, as well as impaired gamma synchronization, abnormal spine morphology, and reduced levels of NMDAR subunits in amygdala. Social approach deficits in Pcdh10+/− males were rescued with acute treatment with the NMDAR partial agonist d-cycloserine. Our studies reveal that male Pcdh10+/− mice have synaptic and behavioral deficits, and establish Pcdh10+/− mice as a novel genetic model for investigating neural circuitry and behavioral changes relevant to ASD.
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DOI：
10.1002/ar.21318
发表时间：
2011-10
影响因子：
2
作者：
Fairless, Andrew H.;Shah, Rhia Y.;Guthrie, Ashley J.;Li, Hongzhe;Brodkin, Edward S.
通讯作者：
Brodkin, Edward S.
影响因子：
2.7
作者：
Fairless, Andrew H.;Katz, Julia M.;Vijayvargiya, Neha;Dow, Holly C.;Kreibich, Arati Sadalge;Berrettini, Wade H.;Abel, Ted;Brodkin, Edward S.
通讯作者：
Brodkin, Edward S.
影响因子：
3.3
作者：
Aoki, E;Kimura, R;Hirano, S
通讯作者：
Hirano, S
影响因子：
14.8
作者：
Carlson, Greg C.;Coulter, Douglas A.
通讯作者：
Coulter, Douglas A.
影响因子：
3.9
作者：
Hartley, Sigan L.;Sikora, Darryn M.
通讯作者：
Sikora, Darryn M.