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Mutations in the presenilin (PS) genes are a predominant cause of familial Alzheimer's disease (fAD). An ortholog of PS in the genetic model organism Caenorhabditis elegans (C. elegans) is sel-12. Mutations in the presenilin genes are commonly thought to lead to fAD by upregulating the expression of amyloid beta (Aβ), however this hypothesis has been challenged by recent evidence. As C. elegans lack amyloid beta (Aβ), the goal of this work was to examine Aβ-independent effects of mutations in sel-12 and PS1/PS2 on behaviour and sensory neuron morphology across the lifespan in a C. elegans model. Olfactory chemotaxis experiments were conducted on sel-12(ok2078) loss-of-function mutant worms. Adult sel-12 mutant worms showed significantly lower levels of chemotaxis to odorants compared to wild-type worms throughout their lifespan, and this deficit increased with age. The chemotaxis phenotype in sel-12 mutant worms is rescued by transgenic over-expression of human wild-type PS1, but not the classic fAD-associated variant PS1C410Y, when expression was driven by either the endogenous sel-12 promoter (Psel-12), a pan-neuronal promoter (Primb-1), or by a promoter whose primary expression was in the sensory neurons responsible for the chemotaxis behavior (Psra-6, Podr-10). The behavioural phenotype was also rescued by over-expressing an atypical fAD-linked mutation in PS1 (PS1ΔS169) that has been reported to leave the Notch pathway intact. An examination of the morphology of polymodal nociceptive (ASH) neurons responsible for the chemotaxis behavior also showed increased neurodegeneration over time in sel-12 mutant worms that could be rescued by the same transgenes that rescued the behaviour, demonstrating a parallel with the observed behavioral deficits. Thus, we report an Aβ-independent neurodegeneration in C. elegans that was rescued by cell specific over-expression of wild-type human presenilin. [ABSTRACT FROM AUTHOR]

This article reviews the literature on learning and memory in the soil-dwelling nematode "Caenorhabditis elegans." Paradigms include nonassociative learning, associative learning, and imprinting, as worms have been shown to habituate to mechanical and chemical stimuli, as well as learn the smells, tastes, temperatures, and oxygen levels that predict aversive chemicals or the presence or absence of food. In each case, the neural circuit underlying the behavior has been at least partially described, and forward and reverse genetics are being used to elucidate the underlying cellular and molecular mechanisms. Several genes have been identified with no known role other than mediating behavior plasticity.

The nervous system is surrounded by an extracellular matrix composed of large glycoproteins, including perlecan, collagens, and laminins. Glial cells in many organisms secrete laminin, a large heterotrimeric protein consisting of anα,β, and γ subunit. Prior studies have found that loss of laminin subunits from vertebrate Schwann cells causes loss of myelination and neuropathies, results attributed to loss of laminin-receptor signaling. We demonstrate that loss of the laminin γ subunit (LanB2) in the peripheral glia of Drosophila melanogaster results in the disruption of glial morphology due to disruption of laminin secretion. Specifically, knockdown of LanB2 in peripheral glia results in accumulation of the β subunit (LanB1), leading to distended endoplasmic reticulum (ER), ER stress, and glial swelling. The physiological consequences of disruption of laminin secretion in glia included decreased larval locomotion and ultimately lethality. Loss of the γ subunit from wrapping glia resulted in a disruption in the glial ensheathment of axons but surprisingly did not affect animal locomotion. We found that Tango1, a protein thought to exclusively mediate collagen secretion, is also important for laminin secretion in glia via a collagen-independent mechanism. However loss of secretion of the laminin trimer does not disrupt animal locomotion. Rather, it is the loss of one subunit that leads to deleterious consequences through the accumulation of the remaining subunits. [ABSTRACT FROM AUTHOR]

Activity-dependent plasticity is a critical component of nervous systems. We show that in Caenorhabditis elegans, worms raised in isolation made smaller responses to mechanosensory stimulation and were smaller and slower to begin laying eggs than age-matched group-raised worms. The glutamate receptor gene GLR-1 was critical for the observed alterations in behavior but not in size, whereas the cGMP-dependent protein kinase gene EGL-4 was critical for the observed changes in size but not the changes in behavior. Mechanosensory stimulation during development reversed the effects of isolation on behavior and began to reduce the effects of isolation on size. In C. elegans, the six mechanosensory touch neurons synapse onto the four pair of command interneurons for forward and backward movement. Touch (mechanosensory) neurons of worms raised in isolation expressed lower levels of green fluorescent protein (GFP)-tagged synaptobrevin than touch neurons of worms raised in colonies. Command interneurons of worms raised in isolation expressed lower levels of GFP-tagged glutamate receptors than command interneurons of worms raised in groups. Brief mechanical stimulation during larval development rescued the expression of GFP-tagged glutamate receptors but not GFP-tagged synaptobrevin. Together, these results indicate that the level of stimulation experienced by C. elegans during development profoundly affects the development of neuronal connectivity and has widespread cellular and behavioral consequences. [ABSTRACT FROM AUTHOR]

Long-term memory for habituation to tap in Caenorhabditis elegans depends on glr-1, a homolog of mammalian non-NMDA glutamate receptors; mutations in glr-1 blocked long-term memory formation. Green fluorescent protein (GFP) constructs were used to visualize glr-1 expression in the interneurons of the mechanosensory circuit and synaptobrevin in the tap sensory neurons of trained and untrained worms. Trained animals had less GLR-1::GFP expression than untrained animals; there was no difference in the vesicle marker synaptobrevin. Heat shock during training blocked both the behavioral expression of long-term memory and the change in GLR-1::GFP expression. Thus, long-term memory in C. elegans is dependent on glr-1 and likely involves changes in the expression or localization of glutamate receptors. [ABSTRACT FROM AUTHOR]