Posttranscriptional regulation of gene expression in learning by the neuronal ELAV-like mRNA-stabilizing proteins

The view that memory is encoded by variations in the strength of synapses implies that long-term biochemical changes take place within subcellular microdomains of neurons. These changes are thought ultimately to be an effect of transcriptional regulation of specific genes. Localized changes, however, cannot be fully explained by a purely transcriptional control of gene expression. The neuron-specific ELAV-like HuB, HuC, and HuD RNA-binding proteins act posttranscriptionally by binding to adenine- and uridine-rich elements (AREs) in the 3′ untranslated region of a set of target mRNAs, and by increasing mRNA cytoplasmic stability and/or rate of translation. Here we show that neuronal ELAV-like genes undergo a sustained up-regulation in hippocampal pyramidal cells only of mice and rats that have learned a spatial discrimination paradigm. This learning-specific increase of ELAV-like proteins was localized within cytoplasmic compartments of the somata and proximal dendrites and was associated with the cytoskeleton. This increase was also accompanied by enhanced expression of the GAP-43 gene, known to be regulated mainly posttranscriptionally and whose mRNA is demonstrated here to be an in vivo ELAV-like target. Antisense-mediated knockdown of HuC impaired spatial learning performance in mice and induced a concomitant down-regulation of GAP-43 expression. Neuronal ELAV-like proteins could exert learning-induced posttranscriptional control of an array of target genes uniquely suited to subserve substrates of memory storage.

记忆通过突触强度的变化进行编码这一观点，意味着神经元的亚细胞微区（subcellular microdomains）内会发生长期的生化改变。这类改变最终被认为是特定基因转录调控（transcriptional regulation）的结果。然而，单纯的基因转录调控无法完全解释这种局域性的改变。神经元特异性类ELAV的HuB、HuC及HuD RNA结合蛋白（RNA-binding protein）通过结合一组靶信使RNA（mRNA）3'非翻译区（3' untranslated region）内的富含腺嘌呤和尿嘧啶元件（AREs），并提高mRNA的细胞质稳定性和/或翻译速率，从而发挥转录后调控作用。本研究显示，仅在完成空间辨别范式（spatial discrimination paradigm）学习的小鼠和大鼠的海马锥体神经元中，神经元类ELAV基因会出现持续的上调表达。这种学习特异性的类ELAV蛋白表达上调，定位于胞体和近端树突的细胞质区域，并与细胞骨架（cytoskeleton）相关联。该表达上调同时伴随GAP-43基因表达的增强；GAP-43基因主要经转录后调控，本研究证实其mRNA是体内类ELAV蛋白的靶标。反义核苷酸介导的HuC基因敲低会损伤小鼠的空间学习能力，并伴随GAP-43表达的下调。神经元类ELAV蛋白可对一系列靶基因实施学习诱导的转录后调控，这些靶基因恰好能够支撑记忆存储的分子基础。