Rookie Snail Protein LAPS Veteran C/EBP: Net Transcriptional Proceeds for Long-Term Facilitation
Authors: Kristin L. Eckel-Mahan, Daniel R. Storm
Journal: Neuron (2006)

Long-term changes in synaptic plasticity require new protein synthesis. This preview discusses data from Kim et al. (this issues of Neuron) that demonstrate the requirement of a novel, nucleolar protein, LLP (LAPS18-like protein), for the formation of long-term facilitation in Aplysia. LLP binds to and transcriptionally activates C/EBP, thereby promoting the formation of long-term facilitation and behavioral sensitization. Long-term changes in synaptic plasticity require new protein synthesis. This preview discusses data from Kim et al. (this issues of Neuron) that demonstrate the requirement of a novel, nucleolar protein, LLP (LAPS18-like protein), for the formation of long-term facilitation in Aplysia. LLP binds to and transcriptionally activates C/EBP, thereby promoting the formation of long-term facilitation and behavioral sensitization. The formation of long-term memory depends on persistent changes in synaptic structure and efficiency. Although the dependency of long-lasting memory on de novo gene expression is well established (Bailey and Kandel, 1993Bailey C.H. Kandel E.R. Annu. Rev. Physiol. 1993; 55: 397-426Crossref PubMed Scopus (723) Google Scholar, Castellucci et al., 1989Castellucci V.F. Blumenfeld H. Goelet P. Kandel E.R. J. Neurobiol. 1989; 20: 1-9Crossref PubMed Scopus (163) Google Scholar, Davis and Squire, 1984Davis H.P. Squire L.R. Psychol. Bull. 1984; 96: 518-559Crossref PubMed Scopus (1262) Google Scholar), elucidation of the molecular basis of memory remains an intense area of investigation. As additional proteins are found to be necessary for long-term memory, clarification of their roles in synaptic plasticity remains a challenging task. Progress toward these goals depends on research carried out in a variety of organisms, with invertebrates such as Drosophila and Aplysia often leading the way. The marine snail Aplysia is a useful model organism to study transcription-dependent plasticity, due to the small number, but large size, of its neurons and the ability to recapitulate synaptic events involved in its behavior in vitro (Castellucci et al., 1989Castellucci V.F. Blumenfeld H. Goelet P. Kandel E.R. J. Neurobiol. 1989; 20: 1-9Crossref PubMed Scopus (163) Google Scholar). The involuntary reflex withdrawal of the Aplysia gill and siphon following noxious stimuli is potentiated by a shock to the tail, a phenomena known as sensitization. The neural changes that accompany sensitization involve direct, monosynaptic connections from Aplysia mechanosensory neurons to the gill motor neurons (Brunelli et al., 1976Brunelli M. Castellucci V. Kandel E.R. Science. 1976; 194: 1178-1181Crossref PubMed Scopus (352) Google Scholar). While the administration of one shock to the tail induces only short-term facilitation and sensitization, several shocks cause long-term facilitation (LTF) at the synapse involved in the gill-withdrawal reflex (Castellucci et al., 1989Castellucci V.F. Blumenfeld H. Goelet P. Kandel E.R. J. Neurobiol. 1989; 20: 1-9Crossref PubMed Scopus (163) Google Scholar). In this issue of Neuron, Kim and colleagues report that a novel nucleolar transcription factor, ApLLP (LAPS18-like protein), is required for both LTF at the sensory motor synapse as well as long-term behavioral sensitization in Aplysia (Kim et al., 2006Kim H. Lee S.-H. Han J.-H. Lee J.-A. Cheang Y.-H. Chang D.-J. Lee Y.-S. Kaang B.-K. Neuron. 2006; 49 (this issue): 707-718Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar). The discovery that ApLLP contains a nucleolar localization signal (Kim et al., 2003Kim H. Chang D.J. Lee J.A. Lee Y.S. Kaang B.K. Neurosci. Lett. 2003; 343: 134-138Crossref PubMed Scopus (10) Google Scholar) identifies it as one of the few transcription factors in the nucleolus known for something other than its contribution to ribosomal biogenesis. The nucleolus, a distinct subnuclear entity, is the intracellular site for ribosomal RNA (rRNA) transcription and processing. Ribosomal processing includes transcription of ribosomal DNA, processing of ribosomal RNA, as well as the assembly of the ribosomal proteins with rRNA to form the large and small preribosomal subunits. While not segregated from the nucleoplasm by a membrane, the nucleolus is visible as an entity within the nucleus due to the dense fibrillar components surrounded by granules as well as the presence of the ribosomal DNA-containing chromatin structures. It is intriguing to find that a nucleolar transcription factor functions as a molecular switch for the conversion of short-term plasticity into LTF. Kim et al. observed that an increase in ApLLP protein in mechanosensory neurons causes LTF after a stimulus that normally causes short-term sensitization (one serotonin pulse). Subsequently, they found that ApLLP transcriptionally activates the immediate early transcription factor C/EBP. An analysis of the C/EBP promoter indicated that ApLLP binds to one of three cAMP-response elements (CREs) following neuronal activation. C/EBP is known to be required for consolidation of LTF at the sensory motor synapse during the gill-withdrawal reflex in Aplysia (Alberini et al., 1994Alberini C.M. Ghirardi M. Metz R. Kandel E.R. Cell. 1994; 76: 1099-1114Abstract Full Text PDF PubMed Scopus (497) Google Scholar), and it is activated by 5-HT and cAMP during the formation of LTF at this synapse (Alberini et al., 1994Alberini C.M. Ghirardi M. Metz R. Kandel E.R. Cell. 1994; 76: 1099-1114Abstract Full Text PDF PubMed Scopus (497) Google Scholar). Although C/EBP family members have multiple roles in physiological processes, including the development and production of adipocytes (Rosen et al., 2000Rosen E.D. Walkey C.J. Puigserver P. Spiegelman B.M. Genes Dev. 2000; 14: 1293-1307Crossref PubMed Google Scholar), their exact role in synaptic plasticity is still a mystery, and a limited number of C/EBP target genes have been identified in neurons (for a review see Ramji and Foka, 2002Ramji D.P. Foka P. Biochem. J. 2002; 365: 561-575Crossref PubMed Google Scholar). The C/EBPβ message and protein are both increased in the hippocampus following hippocampus-dependent learning (Taubenfeld et al., 2001bTaubenfeld S.M. Wiig K.A. Monti B. Dolan B. Pollonini G. Alberini C.M. J. Neurosci. 2001; 21: 84-91Crossref PubMed Google Scholar). Moreover, inhibition of C/EBPβ expression in the hippocampus by administration of antisense oligonucleotides has been reported to cause severe deficits in hippocampus-dependent memory in mice (Taubenfeld et al., 2001aTaubenfeld S.M. Milekic M.H. Monti B. Alberini C.M. Nat. Neurosci. 2001; 4: 813-818Crossref PubMed Scopus (368) Google Scholar). Because the administration of CRE oligonucleotide decoys completely blocks expression of C/EBPβ during training for contextual memory, increased expression is thought to be mediated through CRE-mediated transcription (Athos et al., 2002Athos J. Impey S. Pineda V.V. Chen X. Storm D.R. Nat. Neurosci. 2002; 5: 1119-1120Crossref PubMed Scopus (126) Google Scholar). The discovery that ApLLP is required for LTF and functions as a link between serotonin activation of adenylyl cyclase and C/EBP expression is an intriguing discovery that underscores the potential importance of this novel protein in the C/EBP signaling cascade. C/EBP has been implicated in synaptic plasticity in both vertebrates and invertebrates using a variety of technologies. The signaling pathway in Aplysia is schematically illustrated in Figure 1. It remains to be seen whether a similar nucleolar mechanism exists in mammalian systems, and this will clearly be an important area of investigation in the future. Other questions remain as well. For example, how does cAMP signaling regulate ApLLP expression? Is the nucleolar localization of ApLLP significant for its pivotal role in the induction of LTF? More broadly, how does an increase in C/EBP protein contribute to long-term changes in synaptic strength during synaptic potentiation? The results of Kim and colleagues are provocative and provide the field with many new avenues to pursue in the future. A Nucleolar Protein ApLLP Induces ApC/EBP Expression Required for Long-Term Synaptic Facilitation in Aplysia NeuronsKim et al.NeuronMarch 02, 2006In BriefIn Aplysia, long-term synaptic plasticity is induced by serotonin (5-HT) or neural activity and requires gene expression. Here, we demonstrate that ApLLP, a novel nucleolus protein, is critically involved in both long-term facilitation (LTF) and behavioral sensitization. Membrane depolarization induced ApLLP expression, which activated ApC/EBP expression through a direct binding to CRE. LTF was produced by a single pulse of 5-HT 30 min after the membrane depolarization. This LTF was blocked when either ApLLP or ApC/EBP were blocked by specific antibodies. Full-Text PDF Open Archive