PDF(Pubmed)
Abstract：
Despite the diverse genetic origins of autism spectrum disorders (ASDs), affected individuals share strikingly similar and correlated behavioural traits that include perceptual and sensory processing challenges. Notably, the severity of these sensory symptoms is often predictive of the expression of other autistic traits. However, the origin of these perceptual deficits remains largely elusive. Here, we show a recurrent impairment in visual threat perception that is similarly impaired in 3 independent mouse models of ASD with different molecular aetiologies. Interestingly, this deficit is associated with reduced avoidance of threatening environments-a nonperceptual trait. Focusing on a common cause of ASDs, the Setd5 gene mutation, we define the molecular mechanism. We show that the perceptual impairment is caused by a potassium channel (Kv1)-mediated hypoexcitability in a subcortical node essential for the initiation of escape responses, the dorsal periaqueductal grey (dPAG). Targeted pharmacological Kv1 blockade rescued both perceptual and place avoidance deficits, causally linking seemingly unrelated trait deficits to the dPAG. Furthermore, we show that different molecular mechanisms converge on similar behavioural phenotypes by demonstrating that the autism models Cul3 and Ptchd1, despite having similar behavioural phenotypes, differ in their functional and molecular alteration. Our findings reveal a link between rapid perception controlled by subcortical pathways and appropriate learned interactions with the environment and define a nondevelopmental source of such deficits in ASD.
摘要：
尽管自闭症谱系障碍（ASDs）的遗传起源不同，受影响的个体具有惊人的相似和相关的行为特征，包括知觉和感官处理挑战。值得注意的是,这些感觉症状的严重程度通常可以预测其他自闭症特征的表达。然而,这些知觉缺陷的起源在很大程度上仍然难以捉摸。这里,我们显示了视觉威胁感知的复发性损害，在3个具有不同分子病因的ASD独立小鼠模型中也有类似的损害。有趣的是,这种缺陷与对威胁性环境的回避减少有关-这是一种非感知特征.专注于自闭症的常见原因，Setd5基因突变，我们定义了分子机制。我们表明，知觉障碍是由钾通道（Kv1）介导的皮质下淋巴结中的兴奋性低下引起的，这对于逃避反应的启动至关重要。背侧导水管周围灰色（dPAG）。靶向药理学Kv1阻断拯救了知觉和位置回避缺陷，将看似无关的性状缺陷与dPAG因果关系联系起来。此外，我们通过证明自闭症模型Cul3和Ptchd1尽管具有相似的行为表型，但表明不同的分子机制收敛于相似的行为表型，它们的功能和分子改变不同。我们的发现揭示了由皮质下途径控制的快速感知与与环境的适当学习互动之间的联系，并定义了ASD中此类缺陷的非发育来源。
