Reimers Jeremy M, Loweth Jessica A, Wolf Marina E
Department of Neuroscience, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL, 60064-3095, USA.
Eur J Neurosci. 2014 Apr;39(7):1159-69. doi: 10.1111/ejn.12422.
Brain-derived neurotrophic factor (BDNF) plays a critical role in plasticity at glutamate synapses and in the effects of repeated cocaine exposure. We recently showed that intracranial injection of BDNF into the rat nucleus accumbens (NAc), a key region for cocaine addiction, rapidly increases α-amino-3-hyroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) surface expression. To further characterize BDNF's role in both rapid AMPAR trafficking and slower, homeostatic changes in AMPAR surface expression, we investigated the effects of acute (30 min) and long-term (24 h) treatment with BDNF on AMPAR distribution in NAc medium spiny neurons from postnatal rats co-cultured with mouse prefrontal cortex neurons to restore excitatory inputs. Immunocytochemical studies showed that acute BDNF treatment increased cell surface GluA1 and GluA2 levels, as well as their co-localization, on NAc neurons. This effect of BDNF, confirmed using a protein crosslinking assay, was dependent on ERK but not AKT signaling. In contrast, long-term BDNF treatment decreased AMPAR surface expression on NAc neurons. Based on this latter result, we tested the hypothesis that BDNF plays a role in AMPAR 'scaling down' in response to a prolonged increase in neuronal activity produced by bicuculline (24 h). Supporting this hypothesis, decreasing BDNF signaling with the extracellular BDNF scavenger TrkB-Fc prevented the scaling down of GluA1 and GluA2 surface levels in NAc neurons normally produced by bicuculline. In conclusion, BDNF exerts bidirectional effects on NAc AMPAR surface expression, depending on duration of exposure. Furthermore, BDNF's involvement in synaptic scaling in the NAc differs from its previously described role in the visual cortex.
脑源性神经营养因子（BDNF）在谷氨酸能突触的可塑性以及反复接触可卡因的效应中发挥着关键作用。我们最近发现，向大鼠伏隔核（NAc，可卡因成瘾的关键区域）颅内注射BDNF，能迅速增加α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）的表面表达。为了进一步阐明BDNF在AMPAR快速转运以及AMPAR表面表达较慢的稳态变化中的作用，我们研究了用BDNF急性（30分钟）和长期（24小时）处理对与小鼠前额叶皮层神经元共培养以恢复兴奋性输入的新生大鼠NAc中等棘状神经元中AMPAR分布的影响。免疫细胞化学研究表明，急性BDNF处理可增加NAc神经元上的细胞表面GluA1和GluA2水平及其共定位。使用蛋白质交联试验证实，BDNF的这种作用依赖于ERK信号通路而非AKT信号通路。相反，长期BDNF处理会降低NAc神经元上的AMPAR表面表达。基于后一结果，我们测试了以下假设：BDNF在响应荷包牡丹碱（24小时）引起的神经元活动长期增加时，在AMPAR“下调”中发挥作用。支持这一假设的是，用细胞外BDNF清除剂TrkB-Fc降低BDNF信号，可防止荷包牡丹碱正常产生的NAc神经元中GluA1和GluA2表面水平的下调。总之，BDNF对NAc AMPAR表面表达具有双向作用，这取决于暴露持续时间。此外，BDNF在NAc突触缩放中的作用与其先前在视觉皮层中描述的作用不同。
