PDF(Pubmed)
Abstract：
Childhood lead (Pb2+) intoxication is a public health problem of global proportion. Lead exposure during development produces multiple effects on the central nervous system including impaired synapse formation, altered synaptic plasticity, and learning deficits. In primary hippocampal neurons in culture and hippocampal slices, Pb2+ exposure inhibits vesicular release and reduces the number of fast-releasing sites, an effect associated with Pb2+ inhibition of NMDA receptor-mediated trans-synaptic Brain-Derived Neurotrophic Factor (BDNF) signaling. The objective of this study was to determine if activation of TrkB, the cognate receptor for BDNF, would rescue Pb2+-induced impairments of vesicular release. Rats were chronically exposed to Pb2+ prenatally and postnatally until 50 days of age. This chronic Pb2+ exposure paradigm enhanced paired-pulse facilitation of synaptic potentials in Schaffer collateral-CA1 synapses in the hippocampus, a phenomenon indicative of reduced vesicular release probability. Decreased vesicular release probability was confirmed by both mean-variance analysis and direct 2-photon imaging of vesicular release from hippocampal slices of rats exposed to Pb2+in vivo. We also found a Pb2+-induced impairment of calcium influx in Schaffer collateral-CA1 synaptic terminals. Intraperitoneal injections of Pb2+ rats with the TrkB receptor agonist 7,8-dihydroxyflavone (5 mg/kg) for 14-15 days starting at postnatal day 35, reversed all Pb2+-induced impairments of presynaptic transmitter release at Schaffer collateral-CA1 synapses. This study demonstrates for the first time that in vivo pharmacological activation of TrkB receptors by small molecules such as 7,8-dihydroxyflavone can reverse long-term effects of chronic Pb2+ exposure on presynaptic terminals, pointing to TrkB receptor activation as a promising therapeutic intervention in Pb2+-intoxicated children.
摘要：
儿童铅（Pb2+）中毒是一个全球性的公共卫生问题。发育过程中铅暴露会对中枢神经系统产生多种影响，包括突触形成受损，突触可塑性改变，和学习缺陷。在培养物中的原代海马神经元和海马切片中，Pb2+暴露抑制囊泡释放并减少快速释放位点的数量，与Pb2+抑制NMDA受体介导的跨突触脑源性神经营养因子(BDNF)信号相关的效应。这项研究的目的是确定是否激活TrkB，BDNF的同源受体，将挽救Pb2+诱导的囊泡释放损伤。大鼠在产前和产后长期暴露于Pb2+直至50日龄。这种慢性Pb2暴露范例增强了海马Schaffer侧支CA1突触中突触电位的成对脉冲促进，表明囊泡释放概率降低的现象。通过均值-方差分析和体内暴露于Pb2的大鼠海马切片的囊泡释放的直接2光子成像证实了囊泡释放概率的降低。我们还发现了Pb2诱导的Schaffer侧支CA1突触末端钙内流的损害。从出生后第35天开始，用TrkB受体激动剂7,8-二羟基黄酮（5mg/kg）腹膜内注射Pb2大鼠14-15天，逆转了所有Pb2诱导的Schaffer侧支CA1突触的突触前递质释放障碍。这项研究首次表明，小分子如7,8-二羟基黄酮对TrkB受体的体内药理激活可以逆转慢性Pb2暴露对突触前终末的长期影响，指出TrkB受体激活是Pb2+中毒儿童的有希望的治疗干预措施。
