Liu F C, Graybiel A M
Department of Life Sciences and Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan 11221 Republic of China.
Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4708-13. doi: 10.1073/pnas.95.8.4708.
The cAMP response element-binding protein (CREB) is an activity-dependent transcription factor that is involved in neural plasticity. The kinetics of CREB phosphorylation have been suggested to be important for gene activation, with sustained phosphorylation being associated with downstream gene expression. If so, the duration of CREB phosphorylation might serve as an indicator for time-sensitive plastic changes in neurons. To screen for regions potentially involved in dopamine-mediated plasticity in the basal ganglia, we used organotypic slice cultures to study the patterns of dopamine- and calcium-mediated CREB phosphorylation in the major subdivisions of the striatum. Different durations of CREB phosphorylation were evoked in the dorsal and ventral striatum by activation of dopamine D1-class receptors. The same D1 stimulus elicited (i) transient phosphorylation (</=15 min) in the matrix of the dorsal striatum; (ii) sustained phosphorylation (</=2 hr) in limbic-related structures including striosomes, the nucleus accumbens, the fundus striati, and the bed nucleus of the stria terminalis; and (iii) prolonged phosphorylation (up to 4 hr or more) in cellular islands in the olfactory tubercle. Elevation of Ca2+ influx by stimulation of L-type Ca2+ channels, NMDA, or KCl induced strong CREB phosphorylation in the dorsal striatum but not in the olfactory tubercle. These findings differentiate the response of CREB to dopamine and calcium signals in different striatal regions and suggest that dopamine-mediated CREB phosphorylation is persistent in limbic-related regions of the neonatal basal ganglia. The downstream effects activated by persistent CREB phosphorylation may include time-sensitive neuroplasticity modulated by dopamine.
环磷腺苷效应元件结合蛋白（CREB）是一种与神经可塑性相关的活性依赖型转录因子。有人认为，CREB磷酸化的动力学过程对基因激活很重要，持续磷酸化与下游基因表达相关。如果真是这样，CREB磷酸化的持续时间可能作为神经元中对时间敏感的可塑性变化的一个指标。为了筛选基底神经节中可能参与多巴胺介导的可塑性的区域，我们使用器官型脑片培养来研究纹状体主要亚区中多巴胺和钙介导的CREB磷酸化模式。通过激活多巴胺D1类受体，在背侧和腹侧纹状体中引发了不同持续时间的CREB磷酸化。相同的D1刺激在背侧纹状体的基质中引发了（i）短暂磷酸化（≤15分钟）；（ii）在包括纹状体小体、伏隔核、纹状体底部和终纹床核在内的边缘相关结构中引发了持续磷酸化（≤2小时）；以及（iii）在嗅结节的细胞岛中引发了延长的磷酸化（长达4小时或更长时间）。通过刺激L型钙通道、NMDA或KCl提高Ca2+内流，在背侧纹状体中诱导了强烈的CREB磷酸化，但在嗅结节中没有。这些发现区分了不同纹状体区域中CREB对多巴胺和钙信号的反应，并表明多巴胺介导的CREB磷酸化在新生基底神经节的边缘相关区域中是持续存在的。由持续的CREB磷酸化激活的下游效应可能包括由多巴胺调节的对时间敏感的神经可塑性。
