Brain region-specific disruption of Shank3 in mice reveals a dissociation for cortical and striatal circuits in autism-related behaviors.
Brain region-specific disruption of Shank3 in mice reveals a dissociation for cortical and striatal circuits in autism-related behaviors.
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DOI：
10.1038/s41398-018-0142-6
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发表时间：
2018-04-27
影响因子：
6.8
通讯作者：
Jiang YH
中科院分区：
文献类型：
--
作者：
Bey AL;Wang X;Yan H;Kim N;Passman RL;Yang Y;Cao X;Towers AJ;Hulbert SW;Duffney LJ;Gaidis E;Rodriguiz RM;Wetsel WC;Yin HH;Jiang YH
我们之前报道了一种新的Shank 3突变小鼠品系，通过在全球范围内删除外显子4−22（Δe4−22）导致Shank 3完全缺失。Δe4−22小鼠表现出强烈的ASD样行为，包括社交和沟通受损，刻板行为和过度修饰增加，以及工具性学习的严重缺陷。然而，这些行为背后的解剖学和神经回路是未知的。我们产生了在前脑、纹状体和纹状体D1和D2细胞中选择性缺失Shank 3的小鼠。这些小鼠被用来询问电路/脑区域和细胞类型的特定作用的Shank 3在自闭症相关行为的表达。采用全细胞膜片钳记录和生化分析方法研究了特定脑区的突触功能和分子变化。我们在纹状体抑制性神经元中发现了Shank 3缺失的小鼠的持续探索行为。相反，在前脑兴奋性神经元中缺失Shank 3的小鼠中观察到自我梳理诱导的病变。然而，这些小鼠的社交、交流和工具性学习行为在很大程度上不受影响，这与全球Δe4−22小鼠的情况不同。我们发现了各自大脑区域的生化和电生理结果的独特变化模式，反映了Shank 3转录调控的复杂性。Homer 1b/c和膜超兴奋性的减少，观察到纹状体的Shank 3损失。相比之下，海马神经元中的Shank 3缺失导致NMDAR电流和含GluN 2B的NMDAR增加。这些结果共同表明，Shank 3可能差异调节控制行为的神经回路。我们的研究支持在ASD相关行为中皮层和纹状体神经元中Shank 3功能的分离，并且它说明了这些行为背后的神经回路机制的复杂性。
We previously reported a new line of Shank3 mutant mice which led to a complete loss of Shank3 by deleting exons 4−22 (Δe4−22) globally. Δe4−22 mice display robust ASD-like behaviors including impaired social interaction and communication, increased stereotypical behavior and excessive grooming, and a profound deficit in instrumental learning. However, the anatomical and neural circuitry underlying these behaviors are unknown. We generated mice with Shank3 selectively deleted in forebrain, striatum, and striatal D1 and D2 cells. These mice were used to interrogate the circuit/brain-region and cell-type specific role of Shank3 in the expression of autism-related behaviors. Whole-cell patch recording and biochemical analyses were used to study the synaptic function and molecular changes in specific brain regions. We found perseverative exploratory behaviors in mice with deletion of Shank3 in striatal inhibitory neurons. Conversely, self-grooming induced lesions were observed in mice with deletion of Shank3 in excitatory neurons of forebrain. However, social, communicative, and instrumental learning behaviors were largely unaffected in these mice, unlike what is seen in global Δe4−22 mice. We discovered unique patterns of change for the biochemical and electrophysiological findings in respective brain regions that reflect the complex nature of transcriptional regulation of Shank3. Reductions in Homer1b/c and membrane hyper-excitability were observed in striatal loss of Shank3. By comparison, Shank3 deletion in hippocampal neurons resulted in increased NMDAR-currents and GluN2B-containing NMDARs. These results together suggest that Shank3 may differentially regulate neural circuits that control behavior. Our study supports a dissociation of Shank3 functions in cortical and striatal neurons in ASD-related behaviors, and it illustrates the complexity of neural circuit mechanisms underlying these behaviors.
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影响因子：
6.2
作者：
Bozdagi O;Sakurai T;Papapetrou D;Wang X;Dickstein DL;Takahashi N;Kajiwara Y;Yang M;Katz AM;Scattoni ML;Harris MJ;Saxena R;Silverman JL;Crawley JN;Zhou Q;Hof PR;Buxbaum JD
通讯作者：
Buxbaum JD
影响因子：
30.8
作者：
Durand, Christelle M.;Betancur, Catalina;Bourgeron, Thomas
通讯作者：
Bourgeron, Thomas
DOI：
10.1002/aur.1529
发表时间：
2016-03
期刊：
Autism research : official journal of the International Society for Autism Research
影响因子：
--
作者：
Jaramillo TC;Speed HE;Xuan Z;Reimers JM;Liu S;Powell CM
通讯作者：
Powell CM
影响因子：
10.6
作者：
Di Martino, Adriana;Kelly, Clare;Grzadzinski, Rebecca;Zuo, Xi-Nian;Mennes, Maarten;Angeles Mairena, Maria;Lord, Catherine;Castellanos, F. Xavier;Milham, Michael P.
通讯作者：
Milham, Michael P.
DOI：
10.1038/nrn.2015.8
发表时间：
2016-01
期刊：
Nature reviews. Neuroscience
影响因子：
--
作者：
Kalueff AV;Stewart AM;Song C;Berridge KC;Graybiel AM;Fentress JC
通讯作者：
Fentress JC