Mutations in GRIN2B, which encodes the GluN2B subunit of NMDA receptors, lead to Autism spectrum disorders (ASD), but the pathophysiological mechanisms remain unclear. Recently, we showed that a GluN2B variant that is associated with severe ASD (GluN2B724t) impairs dendrite morphogenesis. To determine which aspects of dendrite growth are affected by GluN2B724t, we investigated the dynamics of dendrite growth and branching in rat neocortical neurons using time-lapse imaging. GluN2B724t expression shifted branch motility toward retraction and away from extension. GluN2B724t and wild-type neurons formed new branches at similar rates, but mutant neurons exhibited increased pruning of dendritic branches. The observed changes in dynamics resulted in nearly complete elimination of the net expansion of arbor size and complexity that is normally observed during this developmental period. These data demonstrate that ASD-associated mutant GluN2B interferes with dendrite morphogenesis by reducing rates of outgrowth while promoting retraction and subsequent pruning. Because mutant dendrites remain motile and capable of growth, agentsit is possible that reducereducing pruning or promotepromoting dendrite stabilization might provide effective therapeutic strategies for reversingcould overcome dendrite arbor defects in ASD associated with GRIN2B mutations.

中文翻译：

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GluN2B 中与自闭症相关的从头突变通过促进收缩和修剪来破坏生长的树突

编码 NMDA 受体的 GluN2B 亚基的 GRIN2B 突变会导致自闭症谱系障碍 (ASD)，但其病理生理机制仍不清楚。最近，我们发现与严重 ASD (GluN2B724t) 相关的 GluN2B 变体会损害树突的形态发生。为了确定 GluN2B724t 影响树突生长的哪些方面，我们使用延时成像研究了大鼠新皮质神经元中树突生长和分支的动态。GluN2B724t 表达将分支运动转向缩回和远离延伸。GluN2B724t 和野生型神经元以相似的速率形成新的分支，但突变神经元表现出树突分支的修剪增加。观察到的动态变化导致乔木尺寸和复杂性的净膨胀几乎完全消除，这在这个发育时期通常观察到。这些数据表明，与 ASD 相关的突变体 GluN2B 通过降低生长速率同时促进回缩和随后的修剪来干扰树突形态发生。由于突变的树突保持活动性并能够生长，因此减少修剪或促进促进树突稳定的药剂可能为逆转提供有效的治疗策略，从而克服与 GRIN2B 突变相关的 ASD 中的树突乔木缺陷。这些数据表明，与 ASD 相关的突变体 GluN2B 通过降低生长速率同时促进回缩和随后的修剪来干扰树突形态发生。由于突变的树突保持活动性并能够生长，因此减少修剪或促进促进树突稳定的药剂可能为逆转提供有效的治疗策略，从而克服与 GRIN2B 突变相关的 ASD 中的树突乔木缺陷。这些数据表明，与 ASD 相关的突变体 GluN2B 通过降低生长速率同时促进回缩和随后的修剪来干扰树突形态发生。由于突变的树突保持活动性并能够生长，因此减少修剪或促进促进树突稳定的药剂可能为逆转提供有效的治疗策略，从而克服与 GRIN2B 突变相关的 ASD 中的树突乔木缺陷。