Effects of sex and DTNBP1 (dysbindin) null gene mutation on the developmental GluN2B-GluN2A switch in the mouse cortex and hippocampus.
Effects of sex and DTNBP1 (dysbindin) null gene mutation on the developmental GluN2B-GluN2A switch in the mouse cortex and hippocampus.
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DOI：
10.1186/s11689-016-9148-7
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发表时间：
2016
影响因子：
4.9
通讯作者：
Borgmann-Winter KE
中科院分区：
文献类型：
--
作者：
Sinclair D;Cesare J;McMullen M;Carlson GC;Hahn CG;Borgmann-Winter KE
自闭症谱系障碍和精神分裂症等神经发育障碍对男性和女性的影响不同，并且具有高度遗传性。性别和遗传脆弱性如何影响这些疾病的发病机制尚不清楚。 N-甲基-D-天冬氨酸 (NMDA) 受体途径与精神分裂症和自闭症谱系障碍有关，并且在出生后发育过程中在 GluN2B-GluN2A 亚基“开关”水平上发生显着变化（从依赖含 GluN2B 的受体转变为依赖含 GluN2A 的受体）。我们研究了性别和遗传脆弱性（特别是 DTNBP1 [dysbindin；一种可能的精神分裂症易感基因] 的无效突变）是否影响发育中的 GluN2B-GluN2A 转换。采用亚细胞分级分离富集突触后密度 (PSD)，结合蛋白质印迹和激酶测定，研究雄性和雌性 DTNBP1 缺失突变小鼠及其野生型同窝小鼠的皮层和海马中的 GluN2B-GluN2A 开关。使用阶乘方差分析评估性别和 DTNBP1 基因型的主要影响以及与年龄的相互作用。在额叶皮质突触的发育过程中，GluN2B-GluN2A 开关的性别差异出现在与 GluN2B 相关的参数中。不同基因型的雄性表现出较高的 GluN2B:GluN2A 和 GluN2B:GluN1 比率（分别为 p < 0.05 和 p < 0.01）、Y1472 处较高的 GluN2B 磷酸化（p < 0.01）以及较高的 PLCγ 丰度（p < 0.01）和 Fyn (p = 0.055) 相对于女性。相比之下，DTNBP1 的作用仅在海马体中明显。 DTNBP1 缺失小鼠中 GluN2B 的发育轨迹被破坏（基因型 × 年龄相互作用 p < 0.05），突触 GluN2A:GluN1 比率增加 (p < 0.05)，PLCγ 降低 (p < 0.05) 和 Fyn（仅在雌性中； p < 0.0005）与野生型相比。性别和 DTNBP1 突变以大脑区域特异性方式影响突触处的 GluN2B-GluN2A 开关，涉及 pY1472-GluN2B、Fyn 和 PLCγ。这凸显了危险因素可能介导其对 NMDA 受体功能障碍疾病脆弱性的影响的可能机制。本文的在线版本 (doi:10.1186/s11689-016-9148-7) 包含补充材料，可供授权用户使用。
Neurodevelopmental disorders such as autism spectrum disorders and schizophrenia differentially impact males and females and are highly heritable. The ways in which sex and genetic vulnerability influence the pathogenesis of these disorders are not clearly understood. The n-methyl-d-aspartate (NMDA) receptor pathway has been implicated in schizophrenia and autism spectrum disorders and changes dramatically across postnatal development at the level of the GluN2B-GluN2A subunit “switch” (a shift from reliance on GluN2B-containing receptors to reliance on GluN2A-containing receptors). We investigated whether sex and genetic vulnerability (specifically, null mutation of DTNBP1 [dysbindin; a possible susceptibility gene for schizophrenia]) influence the developmental GluN2B-GluN2A switch. Subcellular fractionation to enrich for postsynaptic density (PSD), together with Western blotting and kinase assay, were used to investigate the GluN2B-GluN2A switch in the cortex and hippocampus of male and female DTNBP1 null mutant mice and their wild-type littermates. Main effects of sex and DTNBP1 genotype, and interactions with age, were assessed using factorial ANOVA. Sex differences in the GluN2B-GluN2A switch emerged across development at the frontal cortical synapse, in parameters related to GluN2B. Males across genotypes displayed higher GluN2B:GluN2A and GluN2B:GluN1 ratios (p < 0.05 and p < 0.01, respectively), higher GluN2B phosphorylation at Y1472 (p < 0.01), and greater abundance of PLCγ (p < 0.01) and Fyn (p = 0.055) relative to females. In contrast, effects of DTNBP1 were evident exclusively in the hippocampus. The developmental trajectory of GluN2B was disrupted in DTNBP1 null mice (genotype × age interaction p < 0.05), which also displayed an increased synaptic GluN2A:GluN1 ratio (p < 0.05) and decreased PLCγ (p < 0.05) and Fyn (only in females; p < 0.0005) compared to wild-types. Sex and DTNBP1 mutation influence the GluN2B-GluN2A switch at the synapse in a brain-region-specific fashion involving pY1472-GluN2B, Fyn, and PLCγ. This highlights the possible mechanisms through which risk factors may mediate their effects on vulnerability to disorders of NMDA receptor dysfunction. The online version of this article (doi:10.1186/s11689-016-9148-7) contains supplementary material, which is available to authorized users.