Guilhem D, Dreyfus P A, Makiura Y, Suzuki F, Onteniente B
Institut National de la Santé et de la Recherche Médicale Unité, Créteil, France.
Neuroscience. 1996 Jun;72(4):923-31. doi: 10.1016/0306-4522(96)00005-x.
Neurotrophin gene expression in adult brain varies according to physiological activity and following brain injury, suggesting a role in neuronal maintenance and plasticity. However, the exact roles and mechanisms of action of neurotrophins in the adult brain are still poorly understood. We have recently demonstrated that neurons of the adult mouse dentate gyrus can develop a conspicuous morphogenetic response to intrahippocampal injection of kainic acid. This response is correlated with long-lasting overexpression of the brain-derived neurotrophic factor gene, suggesting a causal relationship between molecular and structural changes. To test this hypothesis, brain-derived neurotrophic factor messenger RNA were sequestered in vivo by administration of antisense oligodeoxynucleotides. When administered before 20 h post-kainate, antisense oligodeoxynucleotides totally prevented the kainate-induced neuronal hypertrophy, while sense or missense sequences had no effect. On the other hand, the hypertrophic response was observed when antisense administration was begun 24 h post-kainate, indicating an involvement of brain-derived neurotrophic factor messenger RNA in the initiation of structural changes, but not in their evolution. The hypertrophy was blocked by inhibition of tyrosine kinase activities by K252a, suggesting an involvement of Trk high affinity receptors. Administration of human recombinant brain-derived neurotrophic factor without previous treatment by kainate failed to induce any morphogenetic response. These results show that a short activation of the brain-derived neurotrophic factor gene can, in association with neuronal activation by kainate, trigger dramatic and long-lasting morphological changes in adult neurons. A physiological role of brain-derived neurotrophic factor in adult brain could therefore be to link, by autocrine/paracrine action, activation of glutamate receptors and neuronal morphological adaptive responses.
神经营养因子基因在成体大脑中的表达会根据生理活动以及脑损伤情况而发生变化，这表明其在神经元维持和可塑性方面发挥着作用。然而，神经营养因子在成体大脑中的确切作用和作用机制仍知之甚少。我们最近证明，成年小鼠齿状回的神经元对海马内注射海藻酸能够产生明显的形态发生反应。这种反应与脑源性神经营养因子基因的长期过度表达相关，提示分子变化与结构变化之间存在因果关系。为了验证这一假设，通过给予反义寡脱氧核苷酸在体内隔离脑源性神经营养因子信使核糖核酸。在海藻酸注射后20小时之前给予反义寡脱氧核苷酸时，其完全阻止了海藻酸诱导的神经元肥大，而正义或错义序列则没有效果。另一方面，在海藻酸注射后24小时开始给予反义寡脱氧核苷酸时观察到肥大反应，这表明脑源性神经营养因子信使核糖核酸参与了结构变化的起始，但不参与其演变过程。K252a抑制酪氨酸激酶活性可阻断肥大反应，提示Trk高亲和力受体参与其中。在未预先用海藻酸处理的情况下给予人重组脑源性神经营养因子未能诱导任何形态发生反应。这些结果表明，脑源性神经营养因子基因的短暂激活与海藻酸引起的神经元激活相关联时，能够触发成年神经元显著且持久的形态变化。因此，脑源性神经营养因子在成体大脑中的生理作用可能是通过自分泌/旁分泌作用，将谷氨酸受体的激活与神经元形态适应性反应联系起来。
