Serotonin 1A receptor-mediated signaling through ERK and PKCα is essential for normal synaptogenesis in neonatal mouse hippocampus.
Serotonin 1A receptor-mediated signaling through ERK and PKCα is essential for normal synaptogenesis in neonatal mouse hippocampus.
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5-羟色胺1A受体介导的信号通过ERK和PKCα对于新生小鼠海马的正常突触发生至关重要。
DOI：
10.1038/tp.2011.58
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发表时间：
2012-01-10
影响因子：
6.8
通讯作者：
Banerjee P
中科院分区：
文献类型：
--
作者：
Mogha A;Guariglia SR;Debata PR;Wen GY;Banerjee P
由于5-HT1A-R基因多态性，突触前5-羟色胺1A受体（5-HT1A-R）的异常表达与人类严重抑郁有关，而小鼠前脑在出生后21天（P21）缺乏这种受体会导致成年期焦虑加剧。这些观察结果共同表明，5-HT1A-R在大脑发育中起着至关重要的作用。为了了解这种现象的机制基础，我们使用了P15时C57BL6小鼠（C57）的海马器官型切片培养，这与新生儿突触发生的高峰期相吻合。海马5-HT1A-R刺激通过丝裂原激活的蛋白激酶同工酶Erk1/2和蛋白激酶C （PKC）的顺序激活，引起PSD95表达和树突棘和突触形成的急剧增加。在C57和Swiss Webster小鼠海马内注入5-HT1A-R激动剂和P15信号抑制剂，发现通过PKCα的相同途径在体内24小时内增加了PSD95的表达和突触发生。此外，海马内注射抗抑郁药氟西汀（一种5 -羟色胺再摄取抑制剂）也通过相同的途径增强了PSD95的表达和突触发生。即使在治疗后5天，也观察到突触发生的增加。最后，与野生型相比，5-HT1A-R（−/−）小鼠海马中的突触明显减少，但向5-HT1A-R（−/−）小鼠注入pkc刺激剂和阿尔茨海默病药物bryostatin以绕过不存在的5-HT1A-R，促进了PSD95的表达和突触的发生。这一被阐明的信号级联解释了5-HT1A-R如何调节海马的雕刻和功能，这可能决定了成人的情感表型。
Aberrant expression of the presynaptic serotonin 1A receptor (5-HT1A-R) because of a polymorphism in the 5-HT1A-R gene is associated with severe depression in human, whereas its absence up to postnatal day 21 (P21) in the forebrain of mice results in heightened anxiety in adulthood. These observations collectively indicate that the 5-HT1A-R has a crucial role in brain development. To understand the mechanistic underpinnings of this phenomenon, we used organotypic slice cultures of hippocampi from C57BL6 mice (C57) at P15, which coincides with the peak of neonatal synaptogenesis. Stimulation of the hippocampal 5-HT1A-R caused a dramatic increase in PSD95 expression and dendritic spine and synapse formation through sequential activation of the mitogen-activated protein kinase isozymes Erk1/2 and protein kinase C (PKC). Intrahippocampal infusion of 5-HT1A-R agonists and signaling inhibitors at P15 revealed that the same pathway through PKCα augments PSD95 expression and synaptogenesis in vivo in 24 h in both C57 as well as Swiss Webster mice. Furthermore, intrahippocampal infusion of the antidepressant fluoxetine, a serotonin reuptake inhibitor, also augmented PSD95 expression and synaptogenesis through the same pathway. This increased synaptogenesis was observed even 5 days after treatment. Finally, compared with the wild type, the 5-HT1A-R(−/−) mice harbor significantly less synapses in the hippocampus, but infusion of the PKC-stimulator and Alzheimer drug bryostatin into the 5-HT1A-R(−/−) mice to bypass the non-existent 5-HT1A-R boosted PSD95 expression and synaptogenesis. The elucidated signaling cascade explains how 5-HT1A-R regulates hippocampal sculpting and function, which may determine the affective phenotype of an adult.
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DOI：
10.1073/pnas.0609307104
发表时间：
2007-03-06
影响因子：
11.1
作者：
Ehrlich, Ingrid;Klein, Matthew;Malinow, Roberto
通讯作者：
Malinow, Roberto
影响因子：
4.8
作者：
Brandon, NJ;Delmas, P;Moss, SJ
通讯作者：
Moss, SJ
影响因子：
4.7
作者：
Adayev, T;El-Sherif, Y;Banerjee, P
通讯作者：
Banerjee, P
影响因子：
3.4
作者：
EVENDEN, JL;ANGEBYMOLLER, K
通讯作者：
ANGEBYMOLLER, K
影响因子：
5.3
作者：
Belmonte, MK;Allen, G;Webb, SJ
通讯作者：
Webb, SJ