For a worm, just a few neurons are sufficient to hold a lifetime of memories, making this simple organism an attractive model for learning about learning. Using C. elegans’ ability to remember sensory cues associated with starvation, Yuichi Iino and colleagues at the University of Tokyo, Japan, have turned up a gene critical to the accumulation of worm wisdom. The gene, casy-1, encodes an ortholog of the human calsyntenin/alcadein proteins, cadherin-like synaptic proteins that have been implicated in memory in humans, and in amyloid precursor protein (APP) processing. The work will appear in this week’s edition of PNAS online.

Like APP, the calsyntenins/alcadeins are type I transmembrane proteins that are proteolytically processed in neurons. In a series of papers published over the last five years, Toshiharu Suzuki and colleagues at Hokkaido University in Japan have reported on the association of APP and calsyntenin 2, which appear to form a complex mediated by the scaffold protein X11/X11L in the brain (Araki et al., 2003). They suggest that calsyntenin 2 is coordinately processed with APP, and can modulate the effects of the APP intracellular domain on gene transcription mediated via Fe65 (Araki et al., 2004). Recently, they reported that alcadein is a kinesin cargo protein that can block transport of APP-containing vesicles and increase Aβ production (Araki et al., 2007).

Genetic evidence for a calsyntenin function in human memory comes from a recent SNP association study that found a polymorphism in human calsyntenin 2 (CLSTN2) links to memory performance in a group of young Swiss adults. However, the association did not replicate in a second cohort of older Americans (see ARF related news story), so its real influence remains to be seen.

In the worm work, lead author Daisuke Ikeda and coworkers took advantage of rudimentary learning behavior of C. elegans to perform a genetic screen for learning mutants. In that organism, exposure to a stimulus such as salt normally triggers chemotaxis. However, if the worms encounter salt (or a temperature or olfactory stimulus) while they are starving, they will subsequently avoid that stimulus. When the investigators screened mutagenized worms, they found a casy-1 mutant that was defective in this salt chemotaxis learning. Additional casy-1 deletion alleles also caused the learning defect, and interfered with learning involving olfactory stimulation and temperature. The mutant worms also showed defects in the ability to integrate two sensory stimuli, as indicated by a failure to cross through an unpleasant chemical to get to an attractive one.

CASY-1 protein was expressed throughout the nervous system, the investigators found. The protein appeared mainly in the cell bodies of neurons, associated with cell membrane and intracellular membranes. Genetic interaction analysis suggested that CASY-1 acts parallel to another pathway previously implicated in salt chemotaxis learning, the insulin-like signaling pathway. In addition, while most neuronal cadherins function in development, CASY-1 seemed to be important for signaling in mature neurons, since the salt chemotaxis phenotype could be rescued by re-expression of intact CASY-1 in just the salt-sensing neurons.

The memory-supporting role of CASY-1 required its proteolytic processing, the researchers showed. Expression of fluorescently tagged CASY-1 revealed that the ectodomain is cleaved in neurons, including the neurons implicated in salt chemotaxis learning. The secreted ectodomain fragment includes the cadherin domains and a central domain whose mutation abolished learning. Surprisingly, expressing just the secreted ectodomain alone in CASY-1 mutant worms was sufficient to restore salt chemotaxis learning; the cytoplasmic and transmembrane portions of the protein were dispensable. The target and functions of the CASY-1 ectodomain remain to be determined.

From this data, the authors propose that CASY-1 functions as the precursor to a learning-modulating neurohormone, whose release from neurons plays a role in learning that may be conserved in mammals. Their findings recall recent data showing that the released APP ectodomain (sAPPα) can reinstate the physiological functions of APP in APP-deficient mice (Ring et al., 2007). In their discussion, Iino and coauthors speculate that the cleaved ectodomains of APP and calsyntenins could work in concert, or in parallel, to modulate learning and memory.—Pat McCaffrey


  1. The authors introduce an intriguing and novel thought on the memory concept in C. elegans. Their major findings in the rudimentary learning behavior of C. elegans, genetic screening for learning mutants and its genetic interaction analysis suggesting proteolytic processing of CASY-1 chiefly involved in learning deficits, are of real interest. Specifically, the conservation pattern in the phylogenetic tree and as a precursor to a learning-modulating neurohormone is of specific interest for recent research.

    The main aspects to be understood are as follows:

    • The role of APP (ortholog of the human cadherin-like synaptic proteins that have been implicated in memory in humans, and in amyloid precursor protein processing) on tau in disrupting memory concepts of worms. There is a lot of debate on these proteins and their role in cognitive dysfunction and memory loss.
    • APP tested in worms will then serve as a suitable model to understand the above phenomenon that will help in interlinking the results with the Alzheimer’s condition.

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News Citations

  1. Thanks for the Memories—KIBRA Alleles Predict Top Memory Performers

Paper Citations

  1. . Novel cadherin-related membrane proteins, Alcadeins, enhance the X11-like protein-mediated stabilization of amyloid beta-protein precursor metabolism. J Biol Chem. 2003 Dec 5;278(49):49448-58. PubMed.
  2. . Coordinated metabolism of Alcadein and amyloid beta-protein precursor regulates FE65-dependent gene transactivation. J Biol Chem. 2004 Jun 4;279(23):24343-54. PubMed.
  3. . The novel cargo Alcadein induces vesicle association of kinesin-1 motor components and activates axonal transport. EMBO J. 2007 Mar 21;26(6):1475-86. PubMed.
  4. . The secreted beta-amyloid precursor protein ectodomain APPs alpha is sufficient to rescue the anatomical, behavioral, and electrophysiological abnormalities of APP-deficient mice. J Neurosci. 2007 Jul 18;27(29):7817-26. PubMed.

Further Reading

No Available Further Reading

Primary Papers

  1. . CASY-1, an ortholog of calsyntenins/alcadeins, is essential for learning in Caenorhabditis elegans. Proc Natl Acad Sci U S A. 2008 Apr 1;105(13):5260-5. PubMed.