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Seung-Hee Lee,
Chae-Seok Lim,
Hyungju Park,
Jin-A Lee,
Jin-Hee Han,
Hyoung Kim,
Ye-Hwang Cheang,
Sue-Hyun Lee,
Yong-Seok Lee,
Hyoung-Gon Ko,
Dong-Hyuk Jang,
Hyongkyu Kim,
Maria C Miniaci, Dusan Bartsch,
Eunjoon Kim,
Craig H Bailey,
Eric R Kandel,
Bong-Kiun Kaang
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ABSTRACT: Repeated pulses of serotonin (5-HT) induce long-term facilitation (LTF) of the synapses between sensory and motor neurons of the gill-withdrawal reflex in Aplysia. To explore how apCAM downregulation at the plasma membrane and CREB-mediated transcription in the nucleus, both of which are required for the formation of LTF, might relate to each other, we cloned an apCAM-associated protein (CAMAP) by yeast two-hybrid screening. We found that 5-HT signaling at the synapse activates PKA which in turn phosphorylates CAMAP to induce the dissociation of CAMAP from apCAM and the subsequent translocation of CAMAP into the nucleus of sensory neurons. In the nucleus, CAMAP acts as a transcriptional coactivator for CREB1 and is essential for the activation of ApC/EBP required for the initiation of LTF. Combined, our data suggest that CAMAP is a retrograde signaling component that translocates from activated synapses to the nucleus during synapse-specific LTF.
Cell 06/2007; 129(4):801-12. · 32.40 Impact Factor
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Jin-A Lee,
Sue-Hyun Lee,
Changhoon Lee,
Deok-Jin Chang,
Yong Lee,
Hyoung Kim,
Ye-Hwang Cheang,
Hyoung-Gon Ko,
Yong-Seok Lee,
Heejung Jun, Dusan Bartsch,
Eric R Kandel,
Bong-Kiun Kaang
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ABSTRACT: Long-term memory requires transcriptional regulation by a combination of positive and negative transcription factors. Aplysia activating factor (ApAF) is known to be a positive transcription factor that forms heterodimers with ApC/EBP and ApCREB2. How these heterodimers are regulated and how they participate in the consolidation of long-term facilitation (LTF) has not, however, been characterized. We found that the functional activation of ApAF required phosphorylation of ApAF by PKA on Ser-266. In addition, ApAF lowered the threshold of LTF by forming a heterodimer with ApCREB2. Moreover, once activated by PKA, the ApAF-ApC/EBP heterodimer transactivates enhancer response element-containing genes and can induce LTF in the absence of CRE- and CREB-mediated gene expression. Collectively, these results suggest that PKA-activated ApAF-ApC/EBP heterodimer is a core downstream effector of ApCREB in the consolidation of LTF.
The Journal of Cell Biology 10/2006; 174(6):827-38. · 10.26 Impact Factor
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Amy Chen,
Isabel A Muzzio,
Gaël Malleret, Dusan Bartsch,
Miguel Verbitsky,
Paul Pavlidis,
Amanda L Yonan,
Svetlana Vronskaya,
Michael B Grody,
Ivan Cepeda,
T Conrad Gilliam,
Eric R Kandel
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ABSTRACT: To examine the role of C/EBP-related transcription factors in long-term synaptic plasticity and memory storage, we have used the tetracycline-regulated system and expressed in the forebrain of mice a broad dominant-negative inhibitor of C/EBP (EGFP-AZIP), which preferentially interacts with several inhibiting isoforms of C/EBP. EGFP-AZIP also reduces the expression of ATF4, a distant member of the C/EBP family of transcription factors that is homologous to the Aplysia memory suppressor gene ApCREB-2. Consistent with the removal of inhibitory constraints on transcription, we find an increase in the pattern of gene transcripts in the hippocampus of EGFP-AZIP transgenic mice and both a reversibly enhanced hippocampal-based spatial memory and LTP. These results suggest that several proteins within the C/EBP family including ATF4 (CREB-2) act to constrain long-term synaptic changes and memory formation. Relief of this inhibition lowers the threshold for hippocampal-dependent long-term synaptic potentiation and memory storage in mice.
Neuron 09/2003; 39(4):655-69. · 14.74 Impact Factor
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ABSTRACT: The pathology of trisomy 21/Down syndrome includes cognitive and memory deficits. Increased expression of the dual-specificity protein kinase DYRK1A kinase (DYRK1A) appears to play a significant role in the neuropathology of Down syndrome. To shed light on the cellular role of DYRK1A and related genes we identified three DYRK/minibrain-like genes in the genome sequence of Caenorhabditis elegans, termed mbk-1, mbk-2, and hpk-1. We found these genes to be widely expressed and to localize to distinct subcellular compartments. We isolated deletion alleles in all three genes and show that loss of mbk-1, the gene most closely related to DYRK1A, causes no obvious defects, while another gene, mbk-2, is essential for viability. The overexpression of DYRK1A in Down syndrome led us to examine the effects of overexpression of its C. elegans ortholog mbk-1. We found that animals containing additional copies of the mbk-1 gene display behavioral defects in chemotaxis toward volatile chemoattractants and that the extent of these defects correlates with mbk-1 gene dosage. Using tissue-specific and inducible promoters, we show that additional copies of mbk-1 can impair olfaction cell-autonomously in mature, fully differentiated neurons and that this impairment is reversible. Our results suggest that increased gene dosage of human DYRK1A in trisomy 21 may disrupt the function of fully differentiated neurons and that this disruption is reversible.
Genetics 03/2003; 163(2):571-80. · 4.01 Impact Factor
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ABSTRACT: Interactions between ApCREB1a, ApCREB2, and ApC/EBP have been studied using conventional methods such as the yeast two-hybrid system. However, it is unclear whether these memory-related transcription factors actually interact in the native environment in neurons. To clarify this question, we have developed an Aplysia two-hybrid system and found, consistent with previous studies that ApCREB2 interacts with ApCREB1a and ApC/EBP, and that ApC/EBP forms homodimers. We have also found that ApCREB1a and ApC/EBP do not interact. Therefore, our study shows that formerly described interactions between the proteins actually occur in the Aplysia neurons and that interactions between these transcription factors are specific.
Learning & Memory 10(1):40-3. · 4.22 Impact Factor
