Altered thalamocortical development in the SAP102 knockout model of intellectual disability.
Altered thalamocortical development in the SAP102 knockout model of intellectual disability.
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DOI：
10.1093/hmg/ddw244
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发表时间：
2016-09-15
影响因子：
3.5
通讯作者：
Daw MI
中科院分区：
文献类型：
--
作者：
Crocker-Buque A;Currie SP;Luz LL;Grant SG;Duffy KR;Kind PC;Daw MI
已知导致智力残疾的基因突变集中在特定的基因组中，包括编码突触蛋白的基因和在早期发育过程中表达的基因。我们描述了Dlg3基因缺失对小鼠体感觉皮层发育的影响，Dlg3是一种编码突触nmda受体相互作用蛋白突触相关蛋白102 （SAP102）的id相关基因。SAP102是早期发育中PSD-95家族突触后MAGUK蛋白的主要代表，被认为在稳定未成熟突触受体中发挥作用。SAP102基因缺失导致支配体感觉皮层的丘脑皮质（TC）轴突总数减少，但不影响桶的分离。在突触水平上，SAP102敲除小鼠在TC可塑性的关键时期表现出短暂的NMDA受体动力学加速，尽管glun2b介导的突触传递成分没有减少。这些数据表明受体动力学和NMDA亚基表达之间存在有趣的解离。在关键时期之后，NMDA受体的功能不受SAP102缺失的影响，但TC连接的分化程度有所降低。这些数据表明，由SAP102突变引起的发育早期突触功能的变化会导致生命后期网络连接的变化。
Genetic mutations known to cause intellectual disabilities (IDs) are concentrated in specific sets of genes including both those encoding synaptic proteins and those expressed during early development. We have characterized the effect of genetic deletion of Dlg3, an ID-related gene encoding the synaptic NMDA-receptor interacting protein synapse-associated protein 102 (SAP102), on development of the mouse somatosensory cortex. SAP102 is the main representative of the PSD-95 family of postsynaptic MAGUK proteins during early development and is proposed to play a role in stabilizing receptors at immature synapses. Genetic deletion of SAP102 caused a reduction in the total number of thalamocortical (TC) axons innervating the somatosensory cortex, but did not affect the segregation of barrels. On a synaptic level SAP102 knockout mice display a transient speeding of NMDA receptor kinetics during the critical period for TC plasticity, despite no reduction in GluN2B-mediated component of synaptic transmission. These data indicated an interesting dissociation between receptor kinetics and NMDA subunit expression. Following the critical period NMDA receptor function was unaffected by loss of SAP102 but there was a reduction in the divergence of TC connectivity. These data suggest that changes in synaptic function early in development caused by mutations in SAP102 result in changes in network connectivity later in life.