Dere Ekrem, Dahm Liane, Lu Derek, Hammerschmidt Kurt, Ju Anes, Tantra Martesa, Kästner Anne, Chowdhury Kamal, Ehrenreich Hannelore
Clinical Neuroscience, Max Planck Institute of Experimental Medicine , Göttingen , Germany ; DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB) , Göttingen , Germany.
Clinical Neuroscience, Max Planck Institute of Experimental Medicine , Göttingen , Germany.
Front Behav Neurosci. 2014 May 16;8:181. doi: 10.3389/fnbeh.2014.00181. eCollection 2014.
Autism-spectrum disorders (ASD) are heterogeneous, highly heritable neurodevelopmental conditions affecting around 0.5% of the population across cultures, with a male/female ratio of approximately 4:1. Phenotypically, ASD are characterized by social interaction and communication deficits, restricted interests, repetitive behaviors, and reduced cognitive flexibility. Identified causes converge at the level of the synapse, ranging from mutation of synaptic genes to quantitative alterations in synaptic protein expression, e.g., through compromised transcriptional or translational control. We wondered whether reduced turnover and degradation of synapses, due to deregulated autophagy, would lead to similar phenotypical consequences. Ambra1, strongly expressed in cortex, hippocampus, and striatum, is a positive regulator of Beclin1, a principal player in autophagosome formation. While homozygosity of the Ambra1 null mutation causes embryonic lethality, heterozygous mice with reduced Ambra1 expression are viable, reproduce normally, and lack any immediately obvious phenotype. Surprisingly, comprehensive behavioral characterization of these mice revealed an autism-like phenotype in Ambra1 (+/-) females only, including compromised communication and social interactions, a tendency of enhanced stereotypies/repetitive behaviors, and impaired cognitive flexibility. Reduced ultrasound communication was found in adults as well as pups, which achieved otherwise normal neurodevelopmental milestones. These features were all absent in male Ambra1 (+/-) mice. As a first hint explaining this gender difference, we found a much stronger reduction of Ambra1 protein in the cortex of Ambra1 (+/-) females compared to males. To conclude, Ambra1 deficiency can induce an autism-like phenotype. The restriction to the female gender of autism-generation by a defined genetic trait is unique thus far and warrants further investigation.
自闭症谱系障碍（ASD）具有异质性，是高度可遗传的神经发育疾病，在不同文化背景下影响着约0.5%的人口，男女比例约为4:1。在表型上，ASD的特征是社交互动和沟通缺陷、兴趣受限、重复行为以及认知灵活性降低。已确定的病因集中在突触水平，范围从突触基因的突变到突触蛋白表达的定量改变，例如通过受损的转录或翻译控制。我们想知道，由于自噬失调导致的突触更新和降解减少是否会导致类似的表型后果。Ambra1在皮层、海马体和纹状体中强烈表达，是Beclin1的正向调节因子，而Beclin1是自噬体形成的主要参与者。虽然Ambra1无效突变的纯合子会导致胚胎致死，但Ambra1表达降低的杂合小鼠是存活的，能正常繁殖，且没有任何明显的即时表型。令人惊讶的是，对这些小鼠的全面行为特征分析显示，只有Ambra1（+/-）雌性小鼠呈现出自闭症样表型，包括沟通和社交互动受损、刻板行为/重复行为增强的趋势以及认知灵活性受损。在成年小鼠和幼崽中均发现超声交流减少，而它们在其他方面达到了正常的神经发育里程碑。这些特征在雄性Ambra1（+/-）小鼠中均不存在。作为解释这种性别差异的第一个线索，我们发现与雄性相比，Ambra1（+/-）雌性小鼠皮层中Ambra1蛋白的减少更为明显。总之，Ambra1缺陷可诱发自闭症样表型。由特定遗传特征导致自闭症仅发生在雌性中的情况迄今为止是独特的，值得进一步研究。
