Salama-Cohen Patricia, Arévalo María-Angeles, Grantyn Rosemarie, Rodríguez-Tébar Alfredo
Instituto Cajal de Neurobiología, CSIC, Madrid, Spain.
J Neurochem. 2006 Jun;97(5):1269-78. doi: 10.1111/j.1471-4159.2006.03783.x. Epub 2006 Mar 15.
We have previously shown that dendrite morphology of cultured hippocampal neurones is controlled by Notch receptor activation or binding of nerve growth factor (NGF) to its low affinity receptor p75NTR, i.e. processes that up-regulate the expression of the Homologue of enhancer of split 1 and 5. Thus, the increased expression of these genes decreases the number of dendrites, whereas abrogation of Homologue of enhancer of split 1/5 activity stimulates the outgrowth of new dendrites. Here, we show that Neurogenin 3 is a proneural gene that is negatively regulated by Homologue of enhancer of split 1/5. It also influences dendrite morphology. Hence, a deficit of Notch or NGF/p75NTR activation can lead to the production of high levels of Neurogenin 3, which stimulates the outgrowth of new dendrites. Conversely, activation of either Notch or p75NTR depressed Neurogenin 3 expression, which not only decreased the number of dendrites but also favoured inhibitory (GABAergic) synaptogenesis, thereby diminishing the ratios of excitatory/inhibitory inputs. NGF also augmented the levels of mRNA encoding the vesicular inhibitory amino acid transporter, but it did not affect the fraction of GAD65/67-positive neurones. Conversely, overexpression of Neurogenin 3 largely reduced the number of inhibitory synaptic contacts and, consequently, produced a strong increase in the ratios of excitatory/inhibitory synaptic terminals. Our results reveal a hitherto unknown contribution of NGF/p75NTR to dendritic and synaptic plasticity through Neurogenin 3 signalling.
我们之前已经表明,培养的海马神经元的树突形态受Notch受体激活或神经生长因子(NGF)与其低亲和力受体p75NTR的结合调控,即上调分裂增强子同源物1和5表达的过程。因此,这些基因表达的增加会减少树突的数量,而分裂增强子同源物1/5活性的消除则会刺激新树突的生长。在此,我们表明神经生成素3是一个神经源性基因,受分裂增强子同源物1/5的负调控。它也影响树突形态。因此,Notch或NGF/p75NTR激活的缺乏会导致高水平神经生成素3的产生,从而刺激新树突的生长。相反,Notch或p75NTR的激活会抑制神经生成素3的表达,这不仅会减少树突的数量,还会促进抑制性(GABA能)突触的形成,从而降低兴奋性/抑制性输入的比例。NGF还增加了编码囊泡抑制性氨基酸转运体的mRNA水平,但不影响GAD65/67阳性神经元的比例。相反,神经生成素3的过表达大大减少了抑制性突触接触的数量,因此,导致兴奋性/抑制性突触终末的比例大幅增加。我们的结果揭示了NGF/p75NTR通过神经生成素3信号通路对树突和突触可塑性的前所未知的贡献。