Abstract
Cyclic AMP-responsive element binding protein1 (CREB1) has multiple functions in gene regulation. Various studies have reported that CREB1-dependent gene induction is necessary for memory formation and long-lasting behavioral changes in both vertebrates and invertebrates. In the present study, we characterized Lymnaea CREB1 (LymCREB1) mRNA isoforms of spliced variants in the central nervous system (CNS) of the pond snail Lymnaea stagnalis. Among these spliced variants, the three isoforms that code a whole LymCREB1 protein are considered to be the activators for gene regulation. The other four isoforms, which code truncated LymCREB1 proteins with no kinase inducible domain, are the repressors. For a better understanding of the possible roles of different LymCREB1 isoforms, the expression level of these isoform mRNAs was investigated by a real-time quantitative RT-PCR method. Further, we examined the changes in gene expression for all the isoforms in the CNS after conditioned taste aversion (CTA) learning or backward conditioning as a control. The results showed that CTA learning increased LymCREB1 gene expression, but it did not change the activator/repressor ratio. Our findings showed that the repressor isoforms, as well as the activator ones, are expressed in large amounts in the CNS, and the gene expression of CREB1 isoforms appeared to be specific for the given stimulus. This was the first quantitative analysis of the expression patterns of CREB1 isoforms at the mRNA level and their association with learning behavior.
Highlights
Cyclic AMP-responsive element binding protein (CREB) is a transcription factor regulating a remarkable spectrum of cellular responses involved in developmental events, cell survival, neuronal differentiation, and memory formation in the brains of animal species (Lonze and Ginty, 2002)
CHANGE IN THE COPY NUMBERS OF LymCREB1 ISOFORMS AFTER CONDITIONED TASTE AVERSION LEARNING To investigate the expression of LymCREB1 isoforms in association with learning and memory formation, we further examined the changes in the levels of LymCREB1 isoforms after conditioned taste aversion (CTA) learning in Lymnaea (Kojima et al, 1997)
Previous reports showed that alternatively spliced isoforms of CREB family protein have opposite functions in the induction of long-lasting learning behavior, indicating that the expression level of each isoform is critical for memory formation (Bourtchuladze et al, 1994; Yin et al, 1994; Blöcher et al, 2003, 2005; Perazzona et al, 2004)
Summary
Cyclic AMP-responsive element binding protein (CREB) is a transcription factor regulating a remarkable spectrum of cellular responses involved in developmental events, cell survival, neuronal differentiation, and memory formation in the brains of animal species (Lonze and Ginty, 2002). In Aplysia, at least three different CREB isoforms played competing roles in long-term memory formation (Bartsch et al, 1998; Upadhya et al, 2004). Mohamed et al (2005) and Liu et al (2008) reported that inducing CREB1 gene expression by a direct CREB1 feedback loop leads to increased transcriptional activity for long-term synaptic facilitation in Aplysia. These studies clearly showed that spliced isoforms of CREB regulate the gene induction for memory formation, and the ratio between the levels of CREB activator and repressor isoforms is important for memory formation. There has been no absolute quantitative comparison of the expression levels of CREB isoforms in relation to learning and memory formation
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