Brain Research Centre and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
Neuron. 2013 Aug 21;79(4):680-95. doi: 10.1016/j.neuron.2013.06.029. Epub 2013 Aug 1.
Selective synapse development determines how complex neuronal networks in the brain are formed. Complexes of postsynaptic neuroligins and LRRTMs with presynaptic neurexins contribute widely to excitatory synapse development, and mutations in these gene families increase the risk of developing psychiatric disorders. We find that LRRTM4 has distinct presynaptic binding partners, heparan sulfate proteoglycans (HSPGs). HSPGs are required to mediate the synaptogenic activity of LRRTM4. LRRTM4 shows highly selective expression in the brain. Within the hippocampus, we detected LRRTM4 specifically at excitatory postsynaptic sites on dentate gyrus granule cells. LRRTM4(-/-) dentate gyrus granule cells, but not CA1 pyramidal cells, exhibit reductions in excitatory synapse density and function. Furthermore, LRRTM4(-/-) dentate gyrus granule cells show impaired activity-regulated AMPA receptor trafficking. These results identifying cell-type-specific functions and multiple presynaptic binding partners for different LRRTM family members reveal an unexpected complexity in the design and function of synapse-organizing proteins.
选择性突触发育决定了大脑中复杂的神经网络是如何形成的。突触后神经黏附素和 LRRTM 与突触前神经连接蛋白的复合物广泛促进兴奋性突触发育，这些基因家族的突变增加了患精神疾病的风险。我们发现 LRRTM4 具有独特的突触前结合伴侣，即硫酸乙酰肝素蛋白聚糖（HSPG）。HSPG 介导 LRRTM4 的突触发生活性是必需的。LRRTM4 在大脑中具有高度选择性表达。在海马体中，我们在齿状回颗粒细胞的兴奋性突触后位点特异性检测到 LRRTM4。LRRTM4(-/-) 齿状回颗粒细胞而非 CA1 锥体神经元表现出兴奋性突触密度和功能降低。此外，LRRTM4(-/-) 齿状回颗粒细胞表现出活性调节型 AMPA 受体转运受损。这些结果确定了不同 LRRTM 家族成员的细胞类型特异性功能和多个突触前结合伴侣，揭示了突触组织蛋白的设计和功能具有出乎意料的复杂性。
