Laboratory for Motor Learning Control, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan; Obata Research Unit, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan.
Laboratory for Motor Learning Control, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan.
Neuroscience. 2014 Jan 3;256:242-51. doi: 10.1016/j.neuroscience.2013.10.030. Epub 2013 Oct 21.
In the central nervous system, the normal development of neuronal circuits requires adequate temporal activation of receptors for individual neurotransmitters. Previous studies have demonstrated that α₂-adrenoceptor (α₂-AR) activation eliminates spontaneous action potentials of interneurons in the cerebellar molecular layer (MLIs) and subsequently reduces the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in Purkinje cells (PCs) after the second postnatal week. The magnitude of the α₂-adrenergic reduction in sIPSC frequency is enhanced during the third postnatal week because of an increase in firing-derived sIPSCs. However, little is known about the effects of α₂-AR activation by noradrenaline (NA) on cerebellar GABAergic synaptic transmission that is accompanied by the activation of other AR subtypes, α₁- and β-ARs. Here, we developmentally examined the roles of α₂-AR activation in the noradrenergic facilitation of sIPSCs in cerebellar PCs. Until the second postnatal week, when substantial inhibitory effects of α₂-ARs are absent, NA potentiated sIPSCs and maintained the increased sIPSC frequency, suggesting that NA causes long-lasting facilitation of GABAergic synaptic transmission through α₁- and β-AR activation. After the second postnatal week, NA transiently increased the sIPSC frequency, whereas blocking α₂-ARs sustained the noradrenergic sIPSC facilitation and increase in the firing rate of MLIs, suggesting that α₂-AR activation suppresses the noradrenergic facilitation of GABAergic synaptic transmission. The simultaneous activation of α₁- and β-ARs by their specific agonists mimicked the persistent facilitation of sIPSC frequency, which required extracellular signal-regulated kinase 1/2 activation. These findings indicate that NA acts as a neurotrophic factor that strengthens GABAergic synaptic transmission in the developing cerebellar cortex and that α₂-ARs temporally restrain the noradrenergic facilitation of sIPSCs after GABAergic synaptogenesis.
在中枢神经系统中，神经元回路的正常发育需要个体神经递质受体的适当时间激活。先前的研究表明，α₂-肾上腺素能受体 (α₂-AR) 的激活消除了小脑分子层 (MLIs) 中间神经元的自发动作电位，随后在出生后第二周后降低了浦肯野细胞 (PCs) 中自发性抑制性突触后电流 (sIPSCs) 的频率。由于放电衍生的 sIPSCs 增加，第三周后，α₂-肾上腺素能对 sIPSC 频率的抑制作用增强。然而，对于去甲肾上腺素 (NA) 激活的 α₂-AR 对伴随其他 AR 亚型 (α₁-和 β-AR) 激活的小脑 GABA 能突触传递的影响知之甚少。在这里，我们从发育的角度研究了 α₂-AR 激活在去甲肾上腺素增强小脑 PCs 中 sIPSCs 中的作用。直到出生后第二周，当 α₂-AR 产生实质性抑制作用时，NA 增强了 sIPSCs 并维持了增加的 sIPSC 频率，这表明 NA 通过激活 α₁-和 β-AR 引起 GABA 能突触传递的长期增强。出生后第二周后，NA 短暂增加了 sIPSC 频率，而阻断 α₂-AR 持续维持了去甲肾上腺素增强的 sIPSC 易化和 MLIs 放电率的增加，这表明 α₂-AR 激活抑制了去甲肾上腺素对 GABA 能突触传递的易化。其特定激动剂同时激活 α₁-和 β-AR，模拟了 sIPSC 频率的持久易化，这需要细胞外信号调节激酶 1/2 的激活。这些发现表明，NA 作为一种神经营养因子，增强了发育中的小脑皮层中的 GABA 能突触传递，而 α₂-AR 暂时抑制了 GABA 能突触发生后的去甲肾上腺素增强的 sIPSCs。
