Overexpression of Homer1a in the basal and lateral amygdala impairs fear conditioning and induces an autism-like social impairment.
Overexpression of Homer1a in the basal and lateral amygdala impairs fear conditioning and induces an autism-like social impairment.
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DOI：
10.1186/s13229-016-0077-9
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发表时间：
2016
期刊：
影响因子：
6.2
通讯作者：
Ploski JE
中科院分区：
文献类型：
--
作者：
Banerjee A;Luong JA;Ho A;Saib AO;Ploski JE
自闭症谱系障碍（ASD）代表了一组具有广泛行为障碍（包括社交和沟通缺陷）的异质性障碍。除了这些核心症状外，相当数量的ASD个体表现出更高水平的焦虑，一些研究表明，ASD个体的一个子集具有降低的恐惧条件反射能力。破译自闭症谱系障碍的分子基础具有相当大的挑战性，目前人们对它的了解仍然很少。在这项研究中，我们研究了自闭症样障碍的分子基础上，在环境诱导的ASD动物模型，怀孕大鼠暴露于已知的致畸剂，丙戊酸（VPA），在妊娠第12.5天，随后的后代表现出ASD样症状。我们的分析集中在杏仁核（BLA）的基底核和外侧核上，这是一个被发现与ASD病理学相关的大脑区域。我们使用DNA微阵列对BLA进行了全基因组基因表达分析，以检查VPA暴露动物杏仁核内基因表达的差异。我们使用定量PCR（qRT-PCR）和蛋白质印迹法验证了一个VPA失调的候选基因（Homer 1a）。最后，我们利用腺相关病毒（AAV）在幼稚动物的基底和外侧杏仁核中过表达Homer 1a，随后在与ASD相关的一系列行为测试中检查这些动物，包括听觉恐惧条件反射，社交互动和开放领域。我们的微阵列数据表明，Homer 1a是杏仁核内表现出显着上调的基因之一。我们在多个VPA暴露动物队列中观察到Homer 1a信使RNA（mRNA）和蛋白质增加，表明Homer 1a水平失调可能是VPA暴露动物表现出的一些症状的基础。为了验证这一假设，我们利用病毒介导的方法在BLA神经元内过表达Homer 1a，并发现Homer 1a的过表达损害了听觉恐惧条件反射并减少了社会互动，同时对旷场行为没有影响。这项研究表明，杏仁核Homer 1a的失调可能有助于VPA暴露诱导的一些自闭症样症状。这些发现很有趣，部分原因是Homer 1a影响Shank 3，代谢型谷氨酸受体（mGluR 5）和Homer 1的功能，这些蛋白质以前与ASD相关，表明这些不同的ASD模型可能具有相似的分子基础。本文的在线版本（doi：10.1186/s13229-016-0077-9）包含补充材料，可供授权用户使用。
Autism spectrum disorders (ASDs) represent a heterogeneous group of disorders with a wide range of behavioral impairments including social and communication deficits. Apart from these core symptoms, a significant number of ASD individuals display higher levels of anxiety, and some studies indicate that a subset of ASD individuals have a reduced ability to be fear conditioned. Deciphering the molecular basis of ASD has been considerably challenging and it currently remains poorly understood. In this study we examined the molecular basis of autism-like impairments in an environmentally induced animal model of ASD, where pregnant rats are exposed to the known teratogen, valproic acid (VPA), on day 12.5 of gestation and the subsequent progeny exhibit ASD-like symptoms. We focused our analysis on the basal and lateral nucleus of the amygdala (BLA), a region of the brain found to be associated with ASD pathology. We performed whole genome gene expression analysis on the BLA using DNA microarrays to examine differences in gene expression within the amygdala of VPA-exposed animals. We validated one VPA-dysregulated candidate gene (Homer1a) using both quantitative PCR (qRT-PCR) and western blot. Finally, we overexpressed Homer1a within the basal and lateral amygdala of naïve animals utilizing adeno-associated viruses (AAV) and subsequently examined these animals in a battery of behavioral tests associated with ASD, including auditory fear conditioning, social interaction and open field. Our microarray data indicated that Homer1a was one of the genes which exhibited a significant upregulation within the amygdala. We observed an increase in Homer1a messenger RNA (mRNA) and protein in multiple cohorts of VPA-exposed animals indicating that dysregulation of Homer1a levels might underlie some of the symptoms exhibited by VPA-exposed animals. To test this hypothesis, we overexpressed Homer1a within BLA neurons utilizing a viral-mediated approach and found that overexpression of Homer1a impaired auditory fear conditioning and reduced social interaction, while having no influence on open-field behavior. This study indicates that dysregulation of amygdala Homer1a might contribute to some autism-like symptoms induced by VPA exposure. These findings are interesting in part because Homer1a influences the functioning of Shank3, metabotropic glutamate receptors (mGluR5), and Homer1, and these proteins have previously been associated with ASD, indicating that these differing models of ASD may have a similar molecular basis. The online version of this article (doi:10.1186/s13229-016-0077-9) contains supplementary material, which is available to authorized users.