SSRIs target prefrontal to raphe circuits during development modulating synaptic connectivity and emotional behavior.
SSRIs target prefrontal to raphe circuits during development modulating synaptic connectivity and emotional behavior.
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DOI：
10.1038/s41380-018-0260-9
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发表时间：
2019-05
影响因子：
11
通讯作者：
Gaspar P
中科院分区：
文献类型：
--
作者：
Soiza-Reilly M;Meye FJ;Olusakin J;Telley L;Petit E;Chen X;Mameli M;Jabaudon D;Sze JY;Gaspar P
阻断5-羟色胺转运体的抗抑郁药(SLC6A4/SERT)，选择性5-羟色胺再摄取抑制剂(SSRI)可以改善成年人的情绪，但在围产期使用时会产生自相矛盾的长期效果，增加患焦虑和抑郁的风险。这种发育效应的基础尚不清楚。在这里，我们证明了在小鼠出生后的早期(P0-P10)，SLC6A4/SERT在前额叶皮质(PFC)的5-6层锥体神经元的子集中瞬时表达。PFC-SERT+神经元建立与皮质下靶点的谷氨酸能突触，包括中缝背核的5-羟色胺(5-HT)和GABA神经元。PFC-to-DRN通路在出生后发育，与PFC SLC6A4/SERT表达周期相吻合。完全或皮质特异性消融SERT可增加DRN内5-羟色胺和GABA神经元上功能性PFC-谷氨酸突触的数量。这种从PFC到DRN的超神经支配通过早期接触SSRI，氟西汀(从P2到P14)复制，这也会导致焦虑/抑郁样症状。我们表明，对PFC-SERT+神经元活性的药物遗传学操作双向调节了这些症状，表明PFC功能低下在这些对应激的改变反应中具有因果作用。总体而言，我们的数据确定了在发育过程中作为抗抑郁药物靶点的特定PFC下行回路。我们证明，SERT在这一亚群PFC神经元中的发育表达控制着PFC到DRN回路的突触成熟，而这些回路在早期生命中的重塑调节了成年后对应激的行为反应。
Antidepressants that block the serotonin transporter, (Slc6a4/SERT), selective serotonin reuptake inhibitors (SSRIs) improve mood in adults but have paradoxical long-term effects when administered during perinatal periods, increasing the risk to develop anxiety and depression. The basis for this developmental effect is not known. Here, we show that during an early postnatal period in mice (P0–P10), Slc6a4/SERT is transiently expressed in a subset of layer 5–6 pyramidal neurons of the prefrontal cortex (PFC). PFC-SERT+ neurons establish glutamatergic synapses with subcortical targets, including the serotonin (5-HT) and GABA neurons of the dorsal raphe nucleus (DRN). PFC-to-DRN circuits develop postnatally, coinciding with the period of PFC Slc6a4/SERT expression. Complete or cortex-specific ablation of SERT increases the number of functional PFC glutamate synapses on both 5-HT and GABA neurons in the DRN. This PFC-to-DRN hyperinnervation is replicated by early-life exposure to the SSRI, fluoxetine (from P2 to P14), that also causes anxiety/depressive-like symptoms. We show that pharmacogenetic manipulation of PFC-SERT+ neuron activity bidirectionally modulates these symptoms, suggesting that PFC hypofunctionality has a causal role in these altered responses to stress. Overall, our data identify specific PFC descending circuits that are targets of antidepressant drugs during development. We demonstrate that developmental expression of SERT in this subset of PFC neurons controls synaptic maturation of PFC-to-DRN circuits, and that remodeling of these circuits in early life modulates behavioral responses to stress in adulthood.
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DOI：
10.1073/pnas.0700293104
发表时间：
2007-03-20
影响因子：
11.1
作者：
Armbruster, Blaine N.;Li, Xiang;Roth, Bryan L.
通讯作者：
Roth, Bryan L.
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
34.7
作者：
Arnsten, Amy F. T.
通讯作者：
Arnsten, Amy F. T.
影响因子：
3.7
作者：
Altamura, C.;Dell'Acqua, M. L.;Persico, Antonio M.
通讯作者：
Persico, Antonio M.
影响因子：
64.8
作者：
BLAKELY, RD;BERSON, HE;BRADLEY, CC
通讯作者：
BRADLEY, CC