SLC25A12 expression is associated with neurite outgrowth and is upregulated in the prefrontal cortex of autistic subjects
SLC25A12 expression is associated with neurite outgrowth and is upregulated in the prefrontal cortex of autistic subjects
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DOI：
10.1038/sj.mp.4002120
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发表时间：
2008-04-01
影响因子：
11
通讯作者：
Simonneau, M.
中科院分区：
文献类型：
--
作者：
Lepagnol-Bestel, A-M;Maussion, G.;Simonneau, M.
自闭症是一种神经发育障碍，有很强的遗传成分，可能涉及几个基因。基因组筛选提供了与染色体2 q31-q33连锁的证据，其中包括SLC 25 A12基因。自闭症与SLC 25 A12单核苷酸多态性之间的关联已在多项研究中报道。SLC 25 A12编码在具有高代谢活性的神经元中功能重要的线粒体天冬氨酸/谷氨酸载体。孤独症的神经病理学发现和功能异常已被报道为Brodmann区（BA）46和小脑。我们发现，SLC 25 A12在自闭症患者死后脑组织中的表达比对照组更强，在BA 46前额叶皮层，但不在小脑颗粒细胞中。SLC 25 A12表达在双相情感障碍和精神分裂症患者的大脑亚区中没有改变。SLC 25 A12在发育中的人神经元组织中表达，包括含有兴奋性神经元和新皮质祖细胞的新皮质区域以及产生新皮质抑制性中间神经元的神经节隆起。在妊娠中期，当脑回和脑沟开始发育时，SLC 25 A12分子梯度在外侧前额叶和腹侧颞叶皮层中被确定。这些胎儿结构在自闭症中产生异常活动的区域，包括背外侧前额叶皮层（BA 46），下额叶皮层的盖部和梭状回。SLC 25 A12在小鼠胚胎皮层神经元中的过表达或沉默也改变了树突长度和树突线粒体的移动性。我们的研究结果表明，SLC 25 A12过表达可能参与自闭症的病理生理学，在出生前和出生后阶段，修改特定子区域的神经网络，如背外侧前额叶皮层和梭状回。
Autism is a neurodevelopmental disorder with a strong genetic component, probably involving several genes. Genome screens have provided evidence of linkage to chromosome 2q31-q33, which includes the SLC25A12 gene. Association between autism and single-nucleotide polymorphisms in SLC25A12 has been reported in various studies. SLC25A12 encodes the mitochondrial aspartate/glutamate carrier functionally important in neurons with high-metabolic activity. Neuropathological findings and functional abnormalities in autism have been reported for Brodmann's area (BA) 46 and the cerebellum. We found that SLC25A12 was expressed more strongly in the post-mortem brain tissues of autistic subjects than in those of controls, in the BA46 prefrontal cortex but not in cerebellar granule cells. SLC25A12 expression was not modified in brain subregions of bipolar and schizophrenic patients. SLC25A12 was expressed in developing human neuronal tissues, including neocortical regions containing excitatory neurons and neocortical progenitors and the ganglionic eminences that generate neocortical inhibitory interneurons. At mid-gestation, when gyri and sulci start to develop, SLC25A12 molecular gradients were identified in the lateral prefrontal and ventral temporal cortex. These fetal structures generate regions with abnormal activity in autism, including the dorsolateral prefrontal cortex (BA46), the pars opercularis of the inferior frontal cortex and the fusiform gyrus. SLC25A12 overexpression or silencing in mouse embryonic cortical neurons also modified dendrite length and the mobility of dendritic mitochondria. Our findings suggest that SLC25A12 overexpression may be involved in the pathophysiology of autism, modifying neuronal networks in specific subregions, such as the dorsolateral prefrontal cortex and fusiform gyrus, at both pre-and postnatal stages.