Semaphorin 5A inhibits synaptogenesis in early postnatal- and adult-born hippocampal dentate granule cells.
Semaphorin 5A inhibits synaptogenesis in early postnatal- and adult-born hippocampal dentate granule cells.
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DOI：
10.7554/elife.04390
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发表时间：
2014-10-14
期刊：
影响因子：
7.7
通讯作者：
Giger RJ
中科院分区：
文献类型：
--
作者：
Duan Y;Wang SH;Song J;Mironova Y;Ming GL;Kolodkin AL;Giger RJ
人类SEMAPHORIN 5A（SEMA 5A）是一种自闭症易感基因，但其在大脑发育中的功能尚不清楚。在这项研究中，我们发现，小鼠Sema 5A负调控突触在早期，发育出生，海马齿状颗粒细胞（GC）。Sema 5A由GC强烈表达，并以细胞自主的方式调节树突棘密度。在成年小鼠的大脑中，新生的Sema 5A −/− GC显示树突棘密度增加，AMPA型突触反应增加。Sema 5A通过由GC共表达的丛蛋白A2进行信号传导，并且丛蛋白A2-RasGAP活性是抑制棘发生所必需的。像Sema 5A −/−突变体一样，丛蛋白A2 −/−小鼠显示GC突触能增加，我们发现Sema 5A和丛蛋白A2在GC棘表型方面存在遗传相互作用。Sema 5A-/-小鼠表现出社交互动缺陷，这是自闭症谱系障碍的标志。这些实验鉴定了新的树突内Sema 5A/丛蛋白A2相互作用，其抑制发育中出生和成年出生的GC中的兴奋性突触形成，并且它们为SEMA 5A对自闭症谱系障碍的贡献提供了支持。DOI：http://dx.doi.org/10.7554/eLife.04390.001神经元在称为突触的特殊连接处相互通信。有两种类型的突触，称为兴奋性突触和抑制性突触，两者的密度和强度都受到严格的调节，因为与正常密度和/或强度的微小偏差可能导致疾病。例如，在患有自闭症谱系障碍并表现出社交困难的患者中观察到兴奋性突触过多。编码SEMA 5A蛋白质的基因已被确定为人类自闭症易感基因。SEMA 5A是一种跨膜蛋白，调节神经元之间连接的发育，但目前尚不清楚SEMA 5A基因的突变如何导致自闭症等脑部疾病。现在，Duan等人报道，Sema 5A选择性地抑制小鼠齿状颗粒细胞神经元中兴奋性突触的形成。此外，Sema 5A降低了通过某些颗粒细胞中兴奋性突触的信号的频率和幅度。Sema 5A直接与PlexA 2受体结合，这是一种参与控制突触密度的蛋白质。在行为研究中，与对照动物相比，Sema 5A突变小鼠显示出改变的社会互动模式，不太愿意与不熟悉的小鼠互动。Sema 5A突变小鼠大脑中兴奋性突触数量增加的存在意味着Sema 5A基因的表达通常会阻止过多兴奋性突触的形成。这些动物也表现出改变的社会行为，这一事实表明，无论是由于突触形成增加和/或突触消除减少，过量的突触都可能导致大脑回路的变化，从而产生自闭症谱系障碍的特征行为模式。DOI：http://dx.doi.org/10.7554/eLife.04390.002网站
Human SEMAPHORIN 5A (SEMA5A) is an autism susceptibility gene; however, its function in brain development is unknown. In this study, we show that mouse Sema5A negatively regulates synaptogenesis in early, developmentally born, hippocampal dentate granule cells (GCs). Sema5A is strongly expressed by GCs and regulates dendritic spine density in a cell-autonomous manner. In the adult mouse brain, newly born Sema5A−/− GCs show an increase in dendritic spine density and increased AMPA-type synaptic responses. Sema5A signals through PlexinA2 co-expressed by GCs, and the PlexinA2-RasGAP activity is necessary to suppress spinogenesis. Like Sema5A−/− mutants, PlexinA2−/− mice show an increase in GC glutamatergic synapses, and we show that Sema5A and PlexinA2 genetically interact with respect to GC spine phenotypes. Sema5A−/− mice display deficits in social interaction, a hallmark of autism-spectrum-disorders. These experiments identify novel intra-dendritic Sema5A/PlexinA2 interactions that inhibit excitatory synapse formation in developmentally born and adult-born GCs, and they provide support for SEMA5A contributions to autism-spectrum-disorders. DOI: http://dx.doi.org/10.7554/eLife.04390.001 Neurons communicate with one another at specialized junctions called synapses. There are two types of synapses, called excitatory synapses and inhibitory synapses, and the density and strength of both are tightly regulated because small deviations from the normal density and/or strength may lead to illness. For example, an excess of excitatory synapses has been observed in patients who have autism spectrum disorders and exhibit difficulties in social interaction. The gene that codes for a protein called SEMA5A has been identified as an autism susceptibility gene in humans. SEMA5A is a transmembrane protein that regulates the development of connections between neurons, but it is not known how mutations in the gene for SEMA5A might lead to brain illnesses such as autism spectrum disorders. Now, Duan et al. report that Sema5A selectively inhibits the formation of excitatory synapses in neurons called dentate granule cells in mice. Moreover, Sema5A reduces the frequency and amplitude of the signals that pass through excitatory synapses in certain granule cells. Sema5A directly binds to the receptor PlexA2, a protein that is involved in controlling the density of synapses. In behavioral studies, Sema5A mutant mice displayed altered patterns of social interaction compared to control animals, being less willing to interact with unfamiliar mice. The presence of increased numbers of excitatory synapses in the brains of Sema5A mutant mice implies that expression of the Sema5A gene normally prevents the formation of too many excitatory synapses. The fact that these animals also show altered social behavior suggests that an excess of synapses—whether as a result of increased synapse formation and/or reduced synapse elimination—can lead to changes in brain circuitry that give rise to patterns of behavior that are characteristic of autism spectrum disorders. DOI: http://dx.doi.org/10.7554/eLife.04390.002