中文摘要：

发育中的神经网络需要兼顾生长与稳定这两种相辅相成的需求。稳态可塑性可通过调节兴奋性或抑制性突触传递从而维持神经网络的稳定。已报道的关于稳态可塑性机制方面的研究主要集中在其对兴奋性突触传递的影响,很少关注其对抑制性突触的调控。运用体外培养的原代海马神经元,本项研究发现了持续增强神经元电活动4小时能够诱导抑制性突触传递的稳态上调,且该过程明显早于兴奋性突触的变化。抑制性突触,即γ-氨基丁酸（GABA）突触的改变表现为微小抑制性突触后电流幅度和频率的增加,及GAD65、vGAT和GABAA受体α1亚基等抑制性突触相关蛋白表达的上调。通过在单个神经元中过表达内向整流型钾离子通道Kir2.1从而降低其电活动,发现电活动诱导的神经元自身放电增强对其抑制性突触传递的调节是必须的。与上述结果相互补,在单个神经元中激活过表达的配体门控TRPV1通道,从而直接增强该神经元的自发放电,导致了其抑制性突触传递的增强,模拟了整体增强神经网络电活动的效果。上述结果说明抑制性突触传递的稳态调控依赖于锥体神经元自身电活动的改变,是一种自治性的调节方式。这种调控通过锥体神经元分泌的脑源性神经营养因子（BDNF）逆突触作用于突触前的抑制性神经元末梢,从而增强其自身的抑制性突触输入。通过对幼年大鼠腹腔注射红藻氨酸在体增强神经网络电活动,在海马CA1区域的锥体神经元中诱导出了这种抑制性突触传递的稳态调控。上述结果提示抑制性突触传递的自治性稳态调控是神经元应对网络电活动增强的一个重要代偿性保护机制。

英文摘要：

Developing neural circuits face the dual challenge of growing in an activity-induced fashion and maintaining stability through homeostatic mechanisms.Compared to our understanding of homeostatic regulation of excitatory synapses,relatively little is known about the mechanism mediating homeostatic plasticity of inhibitory synapses,especially that following activity elevation.Here,we found that elevating neuronal activity in cultured hippocampal neurons for 4h significantly increased the frequency and amplitude of mIPSCs,before detectable change at excitatory synapses.Consistently,we observed increases in presynaptic and postsynaptic proteins of GABAergic synapses,including GAD65,vGAT,and GABAARα1.By suppressing activity-induced increase of neuronal firing with expression of the inward rectifier potassium channel Kir2.1 in individual neurons,we showed that elevation in postsynaptic spiking activity is required for activity-dependent increase in the frequency and amplitude of mIPSCs.Importantly,directly elevating spiking in individual postsynaptic neurons,by capsaicin activation of overexpressed TRPV1 channels,was sufficient to induce increased mIPSC amplitude and frequency,mimicking the effect of elevated neuronal activity.Downregulating BDNF expression in the postsynaptic neuron or its extracellular scavenging prevented activity-induced increase in mIPSC frequency,consistent with a role of BDNF-dependent retrograde signaling in this process.Finally,elevating activity in vivo by kainate injection increased both mIPSC amplitude and frequency in CA1 pyramidal neurons.Thus,spiking-induced,cell-autonomous upregulation of GABAergic synaptic inputs,through retrograde BDNF signaling,represents an early adaptive response of neural circuits to elevated network activity.