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The Drosophila cell adhesion molecule Klingon is required for long-term memory formation and is regulated by Notch

Tokyo Metropolitan Institute for Neuroscience, 2-6 Musashidai, Fuchu, Tokyo 183-8526, Japan.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 01/2009; 106(1):310-5. DOI: 10.1073/pnas.0807665106
Source: PubMed

ABSTRACT The ruslan (rus) mutant was previously identified in a behavioral screen for mutants defective in long-lasting memory, which consists of two consolidated memory types, anesthesia-resistant memory, and protein synthesis-dependent long-term memory (LTM). We demonstrate here that rus is a new allele of klingon (klg), which encodes a homophilic cell adhesion molecule. Klg is acutely required for LTM but not anesthesia-resistant memory formation, and Klg expression increases upon LTM induction. LTM formation also requires activity of the Notch cell-surface receptor. Although defects in Notch have been implicated in memory loss because of Alzheimer's disease, downstream signaling linking Notch to memory have not been determined. Strikingly, we found that Notch activity increases upon LTM induction and regulates Klg expression. Furthermore, Notch-induced enhancement of LTM is disrupted by a klg mutation. We propose that Klg is a downstream effector of Notch signaling that links Notch activity to memory.

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    • "Several studies implicate Notch signaling in adult synaptic plasticity, learning, and memory [reviewed in (Costa, Drew, & Silva, 2005)]. For instance, increasing Notch function enhances long-term memory formation, whereas disrupting Notch inhibits memory formation in Drosophila across several paradigms (Ge et al., 2004; Matsuno, Horiuchi, Tully, & Saitoe, 2009; Presente, Boyles, Serway, de Belle, & Andres, 2004). Consistent with this, long-term potentiation (LTP), argued to be a cellular correlate of memory formation, is impaired in mice with reduced Notch1 protein in the hippocampus [produced by expressing antisense directed against Notch1 mRNA] (Wang et al., 2004). "
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    ABSTRACT: It is well-known that Notch signaling plays a critical role in brain development and growing evidence implicates this signaling pathway in adult synaptic plasticity and memory formation. The Notch1 receptor is activated by two subclasses of ligands, Delta-like (including Dll1 and Dll4) and Jagged (including Jag1 and Jag2). Ligand-induced Notch1 receptor signaling is modulated by a family of Fringe proteins, including Lunatic fringe (Lfng). Although Dll1, Jag1 and Lfng are critical regulators of Notch signaling, their relative contribution to memory formation in the adult brain is unknown. To investigate the roles of these important components of Notch signaling in memory formation, we examined spatial and fear memory formation in adult mice with reduced expression of Dll1, Jag1, Lfng and Dll1 plus Lfng. We also examined motor activity, anxiety-like behavior and sensorimotor gating using the acoustic startle response in these mice. Of the lines of mutant mice tested, we found that only mice with reduced Jag1 expression (mice heterozygous for a null mutation in Jag1, Jag1(+/-)) showed a selective impairment in spatial memory formation. Importantly, all other behavior including open field activity, conditioned fear memory (both context and discrete cue), acoustic startle response and prepulse inhibition, was normal in this line of mice. These results provide the first in vivo evidence that Jag1-Notch signaling is critical for memory formation in the adult brain.
    Neurobiology of Learning and Memory 07/2013; 105. DOI:10.1016/j.nlm.2013.07.001 · 4.04 Impact Factor
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    • "A third mutant, D0417, is within the Klingon (Klg) gene that encodes a member of the immunoglobulin superfamily of cell adhesion molecules and has also been implicated in photoreceptor development (Butler et al., 1997). Klg has been shown to be acutely required for LTM and regulated by Notch (Matsuno et al., 2009). Oskar is involved in the translocation of mRNA to the posterior pole during oocyte development and assembly of the germ plasm (Ephrussi and Lehmann, 1992; Lehmann and Ephrussi, 1994). "
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    ABSTRACT: A prior screen identified dozens of Drosophila melanogaster mutants that possess defective long-term memory (LTM). Using spaced olfactory conditioning, we trained 26 of these mutant lines to associate an odor cue with electric shock and then examined the memory of this conditioning 24 h later. All of the mutants tested revealed a deficit in LTM compared to the robust LTM observed in control flies. We used in vivo functional optical imaging to measure the magnitude of a previously characterized LTM trace, which is manifested as increased calcium influx into the axons of α/β mushroom body neurons in response to the conditioned odor. This memory trace was defective in all 26 of the LTM mutants. These observations elevate the significance of this LTM trace given that 26 independent mutants all exhibit a defect in the trace, and further suggest that the calcium trace is a fundamental mechanism underlying Drosophila LTM.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 04/2011; 31(15):5643-7. DOI:10.1523/JNEUROSCI.3190-10.2011 · 6.75 Impact Factor
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    • "Several genes were also found to specifically influence LTM, such as nmda (Xia et al., 2005), crammer (Comas et al., 2004), nf1 (Ho et al., 2007), notch (Ge et al., 2004; Presente et al., 2004), AKAP Yu (Lu et al., 2007), Klingon (Matsuno et al., 2009), and ben (Zhao et al., 2009). Moreover, microarray analysis was used to detect gene expression changes at 0, 6, and 24 h between spaced training and massed training groups. "
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    ABSTRACT: The fruit fly, Drosophila melanogaster, is able to discriminate visual landmarks and form visual long-term memory in a flight simulator. Studies focused on the molecular mechanism of long-term memory have shown that memory formation requires mRNA transcription and protein synthesis. However, little is known about the molecular mechanisms underlying the visual learning paradigm. The present study demonstrated that both spaced training procedure (STP) and consecutive training procedure (CTP) would induce long-term memory at 12 hour after training, and STP caused significantly higher 12-h memory scores compared with CTP. Label-free quantification of liquid chromatography-tandem mass spectrometry (LC-MS/MS) and microarray were utilized to analyze proteomic and transcriptomic differences between the STP and CTP groups. Proteomic analysis revealed 30 up-regulated and 27 down-regulated proteins; Transcriptomic analysis revealed 145 up-regulated and 129 down-regulated genes. Among them, five candidate genes were verified by quantitative PCR, which revealed results similar to microarray. These results provide insight into the molecular components influencing visual long-term memory and facilitate further studies on the roles of identified genes in memory formation.
    Protein & Cell 04/2011; 2(3):215-22. DOI:10.1007/s13238-011-1019-0 · 2.85 Impact Factor
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