Ammar Mohamed Raafet, Thahouly Tamou, Hanauer André, Stegner David, Nieswandt Bernhard, Vitale Nicolas
Institut des Neurosciences Cellulaires et Intégratives (INCI), UPR-3212 Centre National de la Recherche Scientifique &Université de Strasbourg, 5 rue Blaise Pascal, 67084 Strasbourg, France.
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale &Université de Strasbourg, BP 10142, 67404 Illkirch Cedex, France.
Sci Rep. 2015 Oct 6;5:14778. doi: 10.1038/srep14778.
The brain-derived neurotrophic factor BDNF plays a critical role in neuronal development and the induction of L-LTP at glutamatergic synapses in several brain regions. However, the cellular and molecular mechanisms underlying these BDNF effects have not been firmly established. Using in vitro cultures of cortical neurons from knockout mice for Pld1 and Rsk2, BDNF was observed to induce a rapid RSK2-dependent activation of PLD and to stimulate BDNF ERK1/2-CREB and mTor-S6K signalling pathways, but these effects were greatly reduced in Pld1(-/-) neurons. Furthermore, phospho-CREB did not accumulate in the nucleus, whereas overexpression of PLD1 amplified the BDNF-dependent nuclear recruitment of phospho-ERK1/2 and phospho-CREB. This BDNF retrograde signalling was prevented in cells silenced for the scaffolding protein PEA15, a protein which complexes with PLD1, ERK1/2, and RSK2 after BDNF treatment. Finally PLD1, ERK1/2, and RSK2 partially colocalized on endosomal structures, suggesting that these proteins are part of the molecular module responsible for BDNF signalling in cortical neurons.
脑源性神经营养因子（BDNF）在神经元发育以及多个脑区谷氨酸能突触处L-LTP的诱导过程中发挥着关键作用。然而，BDNF产生这些作用的细胞和分子机制尚未完全明确。利用Pld1和Rsk2基因敲除小鼠的皮质神经元进行体外培养，研究发现BDNF可诱导PLD快速发生依赖于RSK2的激活，并刺激BDNF的ERK1/2-CREB和mTor-S6K信号通路，但这些效应在Pld1（-/-）神经元中显著减弱。此外，磷酸化CREB并未在细胞核中积累，而PLD1的过表达增强了BDNF依赖的磷酸化ERK1/2和磷酸化CREB向细胞核的募集。在因支架蛋白PEA15沉默的细胞中，这种BDNF逆行信号传导受到抑制，PEA15是一种在BDNF处理后与PLD1、ERK1/2和RSK2结合的蛋白。最后，PLD1、ERK1/2和RSK2在内体结构上部分共定位，表明这些蛋白是皮质神经元中负责BDNF信号传导的分子模块的一部分。
