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  1. The finding that klingon, a member of the Ig superfamily of cell adhesion molecules, is involved in long-term memory formation is of great interest as it further underlines the necessity of such systems in the structural and functional plasticity necessary for memory consolidation. What is particularly exciting is the finding that klingon expression is dependent on presenilin cleavage of the Notch intracellular domain, as another study has shown Notch and presenilin to become coexpressed at a time when the post-translation glycosylation of the neural cell adhesion molecule (NCAM), another member of the Ig superfamily of cell adhesion molecules, is required for long-term memory formation (Conboy et al., 2007). The suggestion that impaired Notch signaling might be a causal factor for memory impairment in familial AD with presenilin mutations is an attractive idea; however, it must be tempered by the observation that Aβ oligomers are effective only when administered prior to the time when structural modifications occur during memory consolidation (Shankar et al., 2008), and this may account for later defects in Notch signaling. Nevertheless, the recent findings of Matsuno and colleagues give great comfort in the knowledge that these complex and interdependent signaling mechanisms for long-term memory consolidation are common across species and paradigms.

    References:

    Conboy L, Seymour CM, Monopoli MP, O'Sullivan NC, Murphy KJ, Regan CM. Notch signalling becomes transiently attenuated during long-term memory consolidation in adult Wistar rats. Neurobiol Learn Mem. 2007 Oct;88(3):342-51. PubMed.

    Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabatini BL, Selkoe DJ. Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med. 2008 Aug;14(8):837-42. PubMed.

    View all comments by Ciaran Regan

  2. Matsuno et al. identify the gene responsible for the impaired long-term memory (LTM) phenotype in the Drosophila Rus mutant as an allele of klingon which encodes a protein that functions in cell adhesion. Levels of klingon are reduced in Rus mutants, and haploinsufficient klingon mutants exhibit impaired LTM. Moreover, klingon protein levels increase in brains of the flies after they are trained in an LTM task, and adult knockdown of klingon impairs LTM. Interestingly, Matsuno et al. show that klingon protein levels are increased by activation of Notch, a plasma membrane protein believed to play pivotal roles in synaptic plasticity and learning and memory in flies (Presente et al., 2004) and mice (Costa et al., 2003; Wang et al., 2004). They further show that the increase in klingon levels after learning and memory training requires NICD, an intracellular domain of Notch generated by the proteolytic activity of the γ-secretase enzyme complex. Of particular interest for those who study Notch signaling are data showing that NICD regulates klingon protein levels by a post-transcriptional mechanism, because most previous studies suggest that NICD translocates to the nucleus where it acts as a transcriptional regulator. Because previous studies had shown that klingon functions as a cell adhesion molecule, Matsuno et al. propose that klingon acts at synapses to strengthen the connections (physical and/or functional) between presynaptic terminals and post-synaptic dendrites.

    Several questions remain to be answered including 1) What is the molecular basis for post-transcriptional regulation of klingon levels by NICD? For example, does it involve the activity of microRNAs, the protein translational machinery, or perhaps the proteasome? 2) Using a Star Trek analogy, it will be of considerable interest to determine if and how klingons interact with other occupants of the synaptic universe including Vulcans and members of the Starfleet Federation (the latter would include glutamate receptors, calcium channels, neurotrophic factor receptors, etc.); 3) In Drosophila, klingon is a member of the immunoglobulin superfamily that plays a key role in development of photoreceptors (Butler et al., 1997). Is there a mammalian homologue of klingon that plays similar roles in neural development and adult synaptic plasticity? 4) Does the β amyloid precursor intracellular domain (AICD) interact with klingon in a manner similar to NICD? 5) Finally, any novel protein involved in learning and memory is potentially involved in pathological conditions in which synaptic plasticity is impaired, including Alzheimer disease. Future investigations of the klingons and their interactions with other molecular components of neural networks may reveal the next generation of synaptic Starfleet commanders.

    References:

    Presente A, Boyles RS, Serway CN, de Belle JS, Andres AJ. Notch is required for long-term memory in Drosophila. Proc Natl Acad Sci U S A. 2004 Feb 10;101(6):1764-8. PubMed.

    Costa RM, Honjo T, Silva AJ. Learning and memory deficits in Notch mutant mice. Curr Biol. 2003 Aug 5;13(15):1348-54. PubMed.

    Wang Y, Chan SL, Miele L, Yao PJ, Mackes J, Ingram DK, Mattson MP, Furukawa K. Involvement of Notch signaling in hippocampal synaptic plasticity. Proc Natl Acad Sci U S A. 2004 Jun 22;101(25):9458-62. PubMed.

    Butler SJ, Ray S, Hiromi Y. klingon, a novel member of the Drosophila immunoglobulin superfamily, is required for the development of the R7 photoreceptor neuron. Development. 1997 Feb;124(4):781-92. PubMed.

    View all comments by Mark Mattson

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