Patterned vision causes CRE-mediated gene expression in the visual cortex through PKA and ERK
Patterned vision causes CRE-mediated gene expression in the visual cortex through PKA and ERK
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DOI：
10.1523/jneurosci.23-18-07012.2003
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发表时间：
2003-08-06
影响因子：
5.3
通讯作者：
Pizzorusso, T
中科院分区：
文献类型：
--
作者：
Cancedda, L;Putignano, E;Pizzorusso, T
出生后发育过程中正常的视觉经验对于视觉皮层回路的成熟是必要的，并且通过分子机制起作用，但人们对其了解甚少。最近有研究表明，ERK（胞外信号调节激酶）1/2、蛋白激酶A （PKA）和CREB （cAMP反应元件结合蛋白）是视觉皮层经验依赖性发育的关键因素，但对视觉经验在其激活中的作用知之甚少。在这里，我们发现在短暂的黑暗饲养后的视觉刺激导致视觉皮层的短暂ERK激活。视觉诱导的ERK激活主要发生在II-III和VI层的兴奋性神经元中，并通过双眼眼睑缝合来阻止。通过向皮质注入cAMP-PKA抑制剂Rp-8-Cl-cAMPS， ERK磷酸化被强烈降低，从而在PKA和ERK活化之间建立了联系。为了分析ERK和PKA信号的下游影响，我们在CRE （cAMP应答元件）启动子的控制下，研究了视觉刺激对携带LacZ报告基因的转基因小鼠中CREB控制基因转录的作用。视觉刺激引发了cre介导的视觉皮层基因表达的延长，而ERK抑制剂U0126的输注抑制了这一过程。皮质给药rp -8- cl - camp减弱了cre介导的基因转录的经验依赖性激活。这些结果表明，视觉皮质神经元中的ERK磷酸化代表了对模式视觉刺激的分子读出，并且ERK的视觉激活涉及cAMP-PKA系统。最后，由于cre介导的基因表达完全依赖于ERK的激活，我们认为PKA对cre介导的基因表达的作用是由ERK介导的。
Normal visual experience during postnatal development is necessary for the maturation of visual cortical circuits and acts through molecular mechanisms that are still poorly understood. Recently, it has been shown that ERK ( extracellular signal-regulated kinase) 1/2, protein kinase A (PKA), and CREB (cAMP response element-binding protein) are crucial factors for experience-dependent development of the visual cortex, but very little is known about the role of visual experience in their activation. Here, we show that visual stimulation after a brief period of dark rearing caused a transient ERK activation in the visual cortex. Visually induced ERK activation occurred primarily in excitatory neurons of layers II-III and VI and was prevented by binocular lid suture. ERK phosphorylation was strongly reduced by cortical infusion with the cAMP-PKA inhibitor Rp-8-Cl-cAMPS, thus establishing a link between PKA and ERK activation.To analyze the downstream consequences of ERK and PKA signaling, we studied the action of visual stimulation on transcription of genes controlled by CREB in transgenic mice carrying the LacZ reporter gene under the control of the CRE (cAMP response element) promoter. Visual stimulation triggered a prolonged episode of CRE-mediated gene expression in the visual cortex that was suppressed by infusion with the ERK inhibitor U0126. Cortical administration of Rp-8-Cl-cAMPS attenuated the experience-dependent activation of CRE-mediated gene transcription. These results show that ERK phosphorylation in visual cortical neurons represents a molecular readout of patterned visual stimuli and that visual activation of ERK involves the cAMP-PKA system. Finally, because CRE-mediated gene expression was totally dependent on ERK activation, we suggest that PKA action on CRE-mediated gene expression is mediated by ERK.