Distinct roles of neuroligin-1 and SynCAM1 in synapse formation and function in primary hippocampal neuronal cultures.
Distinct roles of neuroligin-1 and SynCAM1 in synapse formation and function in primary hippocampal neuronal cultures.
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DOI：
10.1016/j.neuroscience.2012.04.047
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发表时间：
2012-07-26
期刊：
影响因子：
3.3
通讯作者：
Meriney, S. D.
中科院分区：
文献类型：
--
作者：
Burton, S. D.;Johnson, J. W.;Zeringue, H. C.;Meriney, S. D.
神经连接素是一个家族的细胞粘附分子，在建立适当的中枢神经系统连接的关键;神经连接素信号在体内的破坏沉淀了广泛的认知缺陷。尽管最近取得了相当大的进展，神经连接素-1（NL 1）的具体突触功能仍然不清楚。目前的模型提出，NL 1的行为完全成熟预先存在的突触连接的活动依赖的方式。这种活性依赖性成熟模型的第二个要素是，一种替代分子作用于NL 1的上游，以启动突触连接。SynCAM 1（SC 1）被假设为具有这种功能，尽管关于SC 1功能仍存在一些不确定性。使用过度表达和慢性药理学阻断的突触活动，我们现在证明，NL 1是能够强大的招聘突触蛋白阳性终端独立的突触成熟和活动在2周龄的原代海马神经元培养。我们进一步报告，无论是SC 1的过度表达，也不敲低内源性SC 1影响突触点密度，表明SC 1不是一个限制因素的突触启动成熟的海马神经元在体外。与这些研究结果相一致，我们观察到更大的招聘突触蛋白阳性突触前末梢的NL 1比SC 1在混合培养试验的人工突触之间的原代神经元和异源细胞。总的来说，我们的研究结果主张多个方面的NL 1和SC 1功能的拟议模型，并激励替代模型，SC 1可能成熟的NL 1伪造的突触连接。支持这一模型，我们提出的证据表明，结合NL 1和SC 1过表达触发兴奋性神经退行性变，通过SC 1信号在NL 1启动的突触连接。
Neuroligins are a family of cell adhesion molecules critical in establishing proper central nervous system connectivity; disruption of neuroligin signaling in vivo precipitates a broad range of cognitive deficits. Despite considerable recent progress, the specific synaptic function of neuroligin-1 (NL1) remains unclear. A current model proposes that NL1 acts exclusively to mature pre-existent synaptic connections in an activity-dependent manner. A second element of this activity-dependent maturation model is that an alternate molecule acts upstream of NL1 to initiate synaptic connections. SynCAM1 (SC1) is hypothesized to function in this capacity, though several uncertainties remain regarding SC1 function. Using overexpression and chronic pharmacological blockade of synaptic activity, we now demonstrate that NL1 is capable of robustly recruiting synapsin-positive terminals independent of synaptic maturation and activity in 2-week old primary hippocampal neuronal cultures. We further report that neither SC1 overexpression nor knockdown of endogenous SC1 impacts synapsin punctum densities, suggesting that SC1 is not a limiting factor of synapse initiation in maturing hippocampal neurons in vitro. Consistent with these findings, we observed profoundly greater recruitment of synapsin-positive presynaptic terminals by NL1 than SC1 in a mixed-culture assay of artificial synaptogenesis between primary neurons and heterologous cells. Collectively, our results contend multiple aspects of the proposed model of NL1 and SC1 function and motivate an alternative model whereby SC1 may mature synaptic connections forged by NL1. Supporting this model, we present evidence that combined NL1 and SC1 overexpression triggers excitotoxic neurodegeneration through SC1 signaling at synaptic connections initiated by NL1.
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