Glutamatergic modulation of cerebellar interneuron activity is mediated by an enhancement of GABA release and requires protein kinase A/RIM1alpha signaling.
Glutamatergic modulation of cerebellar interneuron activity is mediated by an enhancement of GABA release and requires protein kinase A/RIM1alpha signaling.
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DOI：
10.1523/jneurosci.2354-08.2009
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发表时间：
2009-01-14
期刊：
影响因子：
--
通讯作者：
Liu SJ
中科院分区：
文献类型：
--
作者：
Lachamp PM;Liu Y;Liu SJ
中枢神经系统中的信息处理是由主神经元和中间神经元组成的神经元网络的活动控制的。对主神经元上突触传递的活动依赖性修饰进行了很好的研究，但对中间神经元之间抑制性传递的调制知之甚少。然而，这个水平的突触可塑性对同步活动的产生有明确的意义。我们已经研究了活动诱导的GABA释放持续增加的分子机制和功能后果，该释放发生在小脑中的抑制性中间神经元（星状细胞）之间。使用全细胞记录和小脑切片，我们发现，刺激神经元的输入（平行纤维）的生理活动模式触发了持久的增加GABA释放星状细胞。这种活动也增强了突触连接的中间神经元之间的抑制性传递。细胞外记录显示，增强的抑制性传递降低了放电频率，改变了星状细胞的动作电位活动模式。GABA释放的持续增加的诱导需要NMDA受体（NMDARs）的激活。通过药理学和遗传学方法，我们发现突触前cAMP/PKA信号传导和活性区蛋白RIM 1 α是持续增强GABA释放所需的关键途径。因此，兴奋性和抑制性传递的突触前可塑性有一个共同的机制。这种抑制性中间神经元之间突触传递的活性依赖性调节可能是中间神经元网络可塑性的重要机制。
Information processing in the CNS is controlled by the activity of neuronal networks composed of principal neurons and interneurons. Activity-dependent modification of synaptic transmission onto principal neurons is well studied, but little is known about the modulation of inhibitory transmission between interneurons. However synaptic plasticity at this level has clear implications for the generation of synchronized activity. We have investigated the molecular mechanism(s) and functional consequences of an activity-induced lasting increase in GABA release that occurs between inhibitory interneurons (stellate cells) in the cerebellum. Using whole cell recording and cerebellar slices, we found that stimulation of glutamatergic inputs (parallel fibres) with a physiological-like pattern of activity triggered a lasting increase in GABA release from stellate cells. This activity also potentiated inhibitory transmission between synaptically connected interneurons. Extracellular recording revealed that the enhanced inhibitory transmission reduced the firing frequency and altered the pattern of action potential activity in stellate cells. The induction of the sustained increase in GABA release required activation of NMDA receptors (NMDARs). Using pharmacological and genetic approaches we found that presynaptic cAMP/PKA signaling and RIM1α, an active zone protein, is the critical pathway that is required for the lasting enhancement of GABA release. Thus a common mechanism can underlie presynaptic plasticity of both excitatory and inhibitory transmission. This activity-dependent regulation of synaptic transmission between inhibitory interneurons may serve as an important mechanism for interneuronal network plasticity.