Beck K D, Lamballe F, Klein R, Barbacid M, Schauwecker P E, McNeill T H, Finch C E, Hefti F, Day J R
Division of Neurogerontology, Andrus Gerontology Center, University of Southern California, Los Angeles 90089-0191.
J Neurosci. 1993 Sep;13(9):4001-14. doi: 10.1523/JNEUROSCI.13-09-04001.1993.
Brain-derived neurotrophic factor (BDNF) and its signal transducing receptor, the TrkB tyrosine protein kinase, are expressed at high levels in the hippocampus of the adult brain, suggesting a role for BDNF mechanisms in neuronal plasticity. To test this hypothesis, we used defined lesions of perforant path and fimbria-fornix, two major hippocampal afferents, to remove synapses on dendrites of dentate gyrus granule cells and pyramidal cells of Ammon's horn and induce synaptic rearrangements. These combined lesions remove afferent connections from entorhinal cortex and septum and produce massive sprouting of axons of the commissural/associational pathways into the molecular layer of the hippocampal dentate gyrus. At days 1, 3, and 6, the lesions decreased BDNF mRNA expression ipsilaterally to approximately 50% of control, with complete recovery at 14 d. The lesions did not alter trkB mRNA levels in neuronal layers of the hippocampus; however, they resulted in a pronounced induction of trkB mRNA expression in hippocampal non-neuronal cells 6-14 d after lesioning. The induction corresponded in time and place to the synaptic reorganization in the lesioned hippocampus. The mRNA species newly induced by the lesions corresponded to those transcripts encoding the noncatalytic TrkB receptor isoform that lacks the cytoplasmic protein kinase domain. Expression of mRNAs coding for neurotrophin-3 and the TrkC tyrosine protein kinase were not altered by the lesions. The findings suggest that truncated noncatalytic TrkB molecules expressed on the surface of glial cells play an important role in plasticity of the adult brain, possibly regulating the concentration of bioactive neurotrophins or the responsiveness of neurotrophin receptors. Alternatively, they may play a role in presenting neurotrophin molecules to growing axons.
脑源性神经营养因子（BDNF）及其信号转导受体TrkB酪氨酸蛋白激酶在成年大脑的海马体中高水平表达，这表明BDNF机制在神经元可塑性中发挥作用。为了验证这一假设，我们利用了穿通通路和穹窿海马伞这两条主要的海马传入纤维的特定损伤，来去除齿状回颗粒细胞和海马角锥体细胞树突上的突触，并诱导突触重排。这些联合损伤去除了来自内嗅皮层和隔区的传入连接，并使连合/联合通路的轴突大量向海马齿状回分子层发芽。在第1、3和6天，损伤使同侧BDNF mRNA表达降低至对照的约50%，14天时完全恢复。损伤并未改变海马神经元层中的trkB mRNA水平；然而，它们导致损伤后6 - 14天海马非神经元细胞中trkB mRNA表达明显诱导。这种诱导在时间和位置上与损伤海马中的突触重组相对应。损伤新诱导的mRNA种类与编码缺乏细胞质蛋白激酶结构域的非催化性TrkB受体亚型的转录本相对应。编码神经营养因子-3和TrkC酪氨酸蛋白激酶的mRNA表达未因损伤而改变。这些发现表明，在胶质细胞表面表达的截短的非催化性TrkB分子在成人大脑的可塑性中起重要作用，可能调节生物活性神经营养因子的浓度或神经营养因子受体的反应性。或者，它们可能在将神经营养因子分子呈递给生长中的轴突方面发挥作用。
