The autism-associated loss of δ-catenin functions disrupts social behavior.
The autism-associated loss of δ-catenin functions disrupts social behavior.
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DOI：
10.1073/pnas.2300773120
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发表时间：
2023-05-30
影响因子：
11.1
通讯作者：
Kim, Seonil
中科院分区：
文献类型：
--
作者：
Mendez-Vazquez, Hadassah;Roach, Regan L.;Nip, Kaila;Chanda, Soham;Sathler, Matheus F.;Garver, Tyler;Danzman, Rosaline A.;Moseley, Madeleine C.;Roberts, Jessica P.;Koch, Olivia N.;Steger, Ava A.;Lee, Rahmi;Arikkath, Jyothi;Kim, Seonil
δ-连环蛋白对谷氨酸能AMPA受体在许多脑区突触的定位和功能具有重要作用。在自闭症患者中发现了δ-连环蛋白基因的甘氨酸34-丝氨酸(G34S)突变，导致δ-连环蛋白功能丧失。δ-Catenin的表达也与其他涉及突触结构和功能的自闭症危险基因密切相关，进一步暗示它在自闭症的发展中起着重要作用。重要的是，社交功能障碍是自闭症的一个关键特征。然而，δ-连环蛋白功能和社会行为之间的联系在很大程度上是未知的。因此，当前研究的意义是通过确定δ-连环蛋白在社会行为中作用的分子、细胞和突触基础来填补这一空白。δ-Catenin在兴奋性突触中表达，并在突触后密度中作为谷氨酸受体(AMPAR)GluA2亚单位的锚。已在自闭症谱系障碍患者中发现δ-连环蛋白基因的甘氨酸34-丝氨酸(G34S)突变，并导致兴奋性突触的δ-连环蛋白功能丧失，这被认为是人类自闭症谱系障碍发病的基础。然而，G34S突变如何导致δ-连环蛋白功能丧失从而诱发自闭症仍不清楚。在这里，利用神经母细胞瘤细胞，我们发现G34S突变增加了依赖于糖原合成酶β(GSK3β)的δ-连环蛋白降解，从而降低了δ-连环蛋白水平，这可能是导致δ-连环蛋白功能丧失的原因之一。携带δ-catenin G34S突变的小鼠大脑皮质中突触的δ-catenin和GluA2水平显著降低。G34S突变增加了皮质兴奋性神经元的谷氨酸能活性，而降低了抑制性中间神经元的谷氨酸能活性，表明细胞的兴奋和抑制发生了变化。δ-catenin G34S突变小鼠也表现出社会功能障碍，这是自闭症的共同特征。最重要的是，对GSK3β活性的药理抑制可以逆转G34S导致的细胞和小鼠δ-连环蛋白功能丧失的影响。最后，利用δ-连环蛋白基因敲除小鼠，我们证实了δ-连环蛋白在β抑制诱导的δ-连环蛋白G34S突变动物的正常社会行为恢复中是必需的。综上所述，我们揭示了由ASD相关的G34S突变引起的δ-Catenin功能的丧失通过改变谷氨酸能活动而导致社会功能障碍，并且GSK3β抑制可以逆转δ-Catenin G34S诱导的突触和行为缺陷。
δ-catenin is important for the localization and function of glutamatergic AMPA receptors at synapses in many brain regions. The glycine 34 to serine (G34S) mutation in the δ-catenin gene has been found in autism patients and results in the loss of δ-catenin functions. δ-catenin expression is also closely linked to other autism-risk genes involved in synaptic structure and function, further implying that it is important for the development of autism. Importantly, social dysfunction is a key characteristic of autism. However, the links between δ-catenin functions and social behavior are largely unknown. The significance of the current research is thus predicated on filling this gap by identifying the molecular, cellular, and synaptic underpinnings of the role of δ-catenin in social behavior. δ-catenin is expressed in excitatory synapses and functions as an anchor for the glutamatergic AMPA receptor (AMPAR) GluA2 subunit in the postsynaptic density. The glycine 34 to serine (G34S) mutation in the δ-catenin gene has been found in autism spectrum disorder (ASD) patients and results in loss of δ-catenin functions at excitatory synapses, which is presumed to underlie ASD pathogenesis in humans. However, how the G34S mutation causes loss of δ-catenin functions to induce ASD remains unclear. Here, using neuroblastoma cells, we identify that the G34S mutation increases glycogen synthase kinase 3β (GSK3β)-dependent δ-catenin degradation to reduce δ-catenin levels, which likely contributes to the loss of δ-catenin functions. Synaptic δ-catenin and GluA2 levels in the cortex are significantly decreased in mice harboring the δ-catenin G34S mutation. The G34S mutation increases glutamatergic activity in cortical excitatory neurons while it is decreased in inhibitory interneurons, indicating changes in cellular excitation and inhibition. δ-catenin G34S mutant mice also exhibit social dysfunction, a common feature of ASD. Most importantly, pharmacological inhibition of GSK3β activity reverses the G34S-induced loss of δ-catenin function effects in cells and mice. Finally, using δ-catenin knockout mice, we confirm that δ-catenin is required for GSK3β inhibition-induced restoration of normal social behavior in δ-catenin G34S mutant animals. Taken together, we reveal that the loss of δ-catenin functions arising from the ASD-associated G34S mutation induces social dysfunction via alterations in glutamatergic activity and that GSK3β inhibition can reverse δ-catenin G34S-induced synaptic and behavioral deficits.
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影响因子：
4.7
作者：
Min WW;Yuskaitis CJ;Yan Q;Sikorski C;Chen S;Jope RS;Bauchwitz RP
通讯作者：
Bauchwitz RP
影响因子：
4.4
作者：
Chen, Ning;Pandya, Nikhil J.;Li, Ka Wan
通讯作者：
Li, Ka Wan
影响因子：
5.3
作者：
Delevich, Kristen;Tucciarone, Jason;Li, Bo
通讯作者：
Li, Bo
影响因子：
11
作者：
Brumback AC;Ellwood IT;Kjaerby C;Iafrati J;Robinson S;Lee AT;Patel T;Nagaraj S;Davatolhagh F;Sohal VS
通讯作者：
Sohal VS
影响因子：
16.2
作者：
Diering GH;Huganir RL
通讯作者：
Huganir RL