Serotonin 5-HT4 receptor boosts functional maturation of dendritic spines via RhoA-dependent control of F-actin
Serotonin 5-HT4 receptor boosts functional maturation of dendritic spines via RhoA-dependent control of F-actin
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DOI：
10.1038/s42003-020-0791-x
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发表时间：
2020-02
影响因子：
5.9
通讯作者：
Yvonne Schill;M. Bijata;O. Kopach;V. Cherkas;Dalia Abdel-Galil;Katrin Böhm;M. Schwab;M. Matsuda;V. Compan;Subhadip Basu;K. Bijata;J. Włodarczyk;Lucie Bard;Nicholas Cole;Alexander E Dityatev;A. Zeug;D. Rusakov;E. Ponimaskin
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作者：
Yvonne Schill;M. Bijata;O. Kopach;V. Cherkas;Dalia Abdel-Galil;Katrin Böhm;M. Schwab;M. Matsuda;V. Compan;Subhadip Basu;K. Bijata;J. Włodarczyk;Lucie Bard;Nicholas Cole;Alexander E Dityatev;A. Zeug;D. Rusakov;E. Ponimaskin
兴奋性连接的活动依赖性重塑支持大脑中的记忆形成。已知血清素受体有助于这种重塑，但对潜在的分子机制仍知之甚少。在这里，我们采用高分辨率的时间推移FRET成像在神经母细胞瘤细胞和神经元树突，以建立5-羟色胺受体5-HT 4（5-HT 4 R）的激活迅速触发空间限制的RhoA活性和G13介导的cofilin磷酸化，从而局部提高丝状肌动蛋白部分。在神经母细胞瘤细胞中，这导致细胞变圆和神经突收缩。在原位海马神经元中，5-HT 4 R介导的RhoA激活触发树突棘的成熟。这是由RhoA依赖性，短暂的细胞兴奋性的变化，反映了自发性突触活动增加，明显分流诱发的突触反应，并增强长时程增强兴奋性传递。因此，5-HT 4 R/G13/RhoA信号转导作为一种以前未被认识的分子途径出现，支持兴奋性突触连接的使用依赖性功能重塑。
Activity-dependent remodeling of excitatory connections underpins memory formation in the brain. Serotonin receptors are known to contribute to such remodeling, yet the underlying molecular machinery remains poorly understood. Here, we employ high-resolution time-lapse FRET imaging in neuroblastoma cells and neuronal dendrites to establish that activation of serotonin receptor 5-HT4(5-HT4R) rapidly triggers spatially-restricted RhoA activity and G13-mediated phosphorylation of cofilin, thus locally boosting the filamentous actin fraction. In neuroblastoma cells, this leads to cell rounding and neurite retraction. In hippocampal neurons in situ, 5-HT4R-mediated RhoA activation triggers maturation of dendritic spines. This is paralleled by RhoA-dependent, transient alterations in cell excitability, as reflected by increased spontaneous synaptic activity, apparent shunting of evoked synaptic responses, and enhanced long-term potentiation of excitatory transmission. The 5-HT4R/G13/RhoA signaling thus emerges as a previously unrecognized molecular pathway underpinning use-dependent functional remodeling of excitatory synaptic connections.