Center for Physiology, Georg-August University and DFG-Research Center of Molecular Physiology of the Brain, D-37073 Göttingen, Germany.
J Physiol. 2009 Nov 1;587(Pt 21):5095-106. doi: 10.1113/jphysiol.2009.178236. Epub 2009 Sep 1.
The development of neuronal networks in the brain requires the differentiation of functional synapses. Neurobeachin (Nbea) was identified as a putative regulator of membrane protein trafficking associated with tubulovesicular endomembranes and postsynaptic plasma membranes. Nbea is essential for evoked transmission at neuromuscular junctions, but its role in the central nervous system has not been characterized. Here, we have studied central synapses of a newly generated gene-trap knockout (KO) mouse line at embryonic day 18, because null-mutant mice are paralysed and die perinatally. Although the overall brain architecture was normal, we identified major abnormalities of synaptic function in mutant animals. In acute slices from the brainstem, both spontaneous excitatory and inhibitory postsynaptic currents were clearly reduced and failure rates of evoked inhibitory responses were markedly increased. In addition, the frequency of miniature excitatory and both the frequency and amplitudes of miniature inhibitory postsynaptic currents were severely diminished in KO mice, indicating a perturbation of both action potential-dependent and -independent transmitter release. Moreover, Nbea appears to be important for the formation and composition of central synapses because the area density of mature asymmetric contacts in the fetal brainstem was reduced to 30% of wild-type levels, and the expression levels of a subset of synaptic marker proteins were smaller than in littermate controls. Our data demonstrate for the first time a function of Nbea at central synapses that may be based on its presumed role in targeting membrane proteins to synaptic contacts, and are consistent with the 'excitatory-inhibitory imbalance' model of autism where Nbea gene rearrangements have been detected in some patients.
脑内神经元网络的发育需要功能性突触的分化。神经海滩蛋白（Nbea）被鉴定为一种假定的膜蛋白运输调节剂，与小管泡内吞小体和突触后质膜相关联。Nbea 对于神经肌肉接头的诱发传递是必需的，但它在中枢神经系统中的作用尚未被描述。在这里，我们研究了一个新生成的基因捕获敲除（KO）小鼠系在胚胎第 18 天的中枢突触，因为纯合突变小鼠在围产期瘫痪和死亡。尽管总体大脑结构正常，但我们在突变动物中发现了突触功能的主要异常。在脑桥的急性切片中，自发兴奋性和抑制性突触后电流明显减少，诱发抑制反应的失败率明显增加。此外，在 KO 小鼠中，微小兴奋性突触的频率以及微小抑制性突触后电流的频率和幅度都严重降低，表明动作电位依赖性和非依赖性递质释放都受到干扰。此外，Nbea 似乎对中枢突触的形成和组成很重要，因为胎脑桥中成熟不对称接触的面积密度减少到野生型水平的 30%，并且突触标记蛋白的一部分表达水平低于同窝对照。我们的数据首次证明了 Nbea 在中枢突触中的作用，这可能基于其在将膜蛋白靶向突触接触方面的假定作用，并且与自闭症的“兴奋性-抑制性失衡”模型一致，在该模型中，一些患者检测到 Nbea 基因重排。
