Neuroligins/LRRTMs prevent activity- and Ca2+/calmodulin-dependent synapse elimination in cultured neurons.
Neuroligins/LRRTMs prevent activity- and Ca2+/calmodulin-dependent synapse elimination in cultured neurons.
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DOI：
10.1083/jcb.201101072
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发表时间：
2011-07-25
期刊：
影响因子：
--
通讯作者：
Südhof TC
中科院分区：
文献类型：
--
作者：
Ko J;Soler-Llavina GJ;Fuccillo MV;Malenka RC;Südhof TC
在培养的神经元中，神经素和富含亮氨酸的重复跨膜蛋白是防止兴奋性突触活性依赖性消除所必需的，突触消除是通过Ca2+/钙调素依赖性途径进行的。神经素（NLs）和富含亮氨酸的重复跨膜蛋白（LRRTMs）是结合突触前神经素的突触后细胞粘附分子。在本文中，我们发现，在培养的海马神经元中，LRRTM1、LRRTM2和/或NL-3的短发夹核糖核酸介导的敲低（KDs）单独或共同作为双或三重KDs （TKDs）并不会减少突触数量。然而，在NL-1敲除小鼠培养的神经元中，LRRTMs和NL-3的TKD诱导兴奋性突触而非抑制性突触损失约40%。引人注目的是，LRRTM/NL缺乏症引发的突触损失被突触活性的慢性阻断以及Ca2+内流或Ca2+/钙调蛋白（CaM）激酶的慢性抑制所消除。此外，CaM的突触后KD以细胞自主的方式阻止突触丢失，这一作用被CaM修复逆转。我们的研究结果表明，两种神经素配体LRRTMs和NLs冗余地维持兴奋性突触，并且由NLs和LRRTMs缺失引起的突触消除由突触活性促进，并由突触后Ca2+/ cam依赖性信号通路介导。
Neuroligins and leucine-rich repeat transmembrane proteins are necessary to prevent activity-dependent elimination of excitatory synapses in cultured neurons, with synapse elimination operating by a Ca2+/calmodulin-dependent pathway. Neuroligins (NLs) and leucine-rich repeat transmembrane proteins (LRRTMs) are postsynaptic cell adhesion molecules that bind to presynaptic neurexins. In this paper, we show that short hairpin ribonucleic acid–mediated knockdowns (KDs) of LRRTM1, LRRTM2, and/or NL-3, alone or together as double or triple KDs (TKDs) in cultured hippocampal neurons, did not decrease synapse numbers. In neurons cultured from NL-1 knockout mice, however, TKD of LRRTMs and NL-3 induced an ∼40% loss of excitatory but not inhibitory synapses. Strikingly, synapse loss triggered by the LRRTM/NL deficiency was abrogated by chronic blockade of synaptic activity as well as by chronic inhibition of Ca2+ influx or Ca2+/calmodulin (CaM) kinases. Furthermore, postsynaptic KD of CaM prevented synapse loss in a cell-autonomous manner, an effect that was reversed by CaM rescue. Our results suggest that two neurexin ligands, LRRTMs and NLs, act redundantly to maintain excitatory synapses and that synapse elimination caused by the absence of NLs and LRRTMs is promoted by synaptic activity and mediated by a postsynaptic Ca2+/CaM-dependent signaling pathway.
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DOI：
10.1523/jneurosci.0470-10.2010
发表时间：
2010-06-02
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Siddiqui TJ;Pancaroglu R;Kang Y;Rooyakkers A;Craig AM
通讯作者：
Craig AM
影响因子：
16.2
作者：
Ko, Jaewon;Fuccillo, Marc V.;Malenka, Robert C.;Suedhof, Thomas C.
通讯作者：
Suedhof, Thomas C.
影响因子：
16.2
作者：
Poulopoulos, Alexandros;Aramuni, Gayane;Varoqueaux, Frederique
通讯作者：
Varoqueaux, Frederique
影响因子：
11.4
作者：
Ko, Jaewon;Zhang, Chen;Suedhof, Thomas C.
通讯作者：
Suedhof, Thomas C.
影响因子：
6.2
作者：
Sousa I;Clark TG;Holt R;Pagnamenta AT;Mulder EJ;Minderaa RB;Bailey AJ;Battaglia A;Klauck SM;Poustka F;Monaco AP;International Molecular Genetic Study of Autism Consortium (IMGSAC)
通讯作者：
International Molecular Genetic Study of Autism Consortium (IMGSAC)