Notch is required for long-term memory in Drosophila

Abstract

A role for Notch in the elaboration of existing neural processes is emerging that is distinct from the increasingly well understood function of this gene in binary cell-fate decisions. Several research groups, by using a variety of organisms, have shown that Notch is important in the development of neural ultrastructure. Simultaneously, Presenilin (Psn) was identified both as a key mediator of Notch signaling and as a site of genetic lesions that cause earlyonset Alzheimer's disease. Here we demonstrate that Notch loss of function produces memory deficits in Drosophila melanogaster. The effects are specific to long-term memory, which is thought to depend on ultrastructural remodeling. We propose that Notch plays an important role in the neural plasticity underlying consolidated memory.W hereas the Notch protein plays an important role in binary cell-fate decisions during development (1), it is also present in the adult brain (2, 3). This finding is particularly interesting in adult Drosophila because the CNS is established by eclosion (4). Given that Notch is not needed for cell-fate decisions in the adult brain, its role in this tissue is unclear.Several groups have shown that Notch is important in the arborization of neuritic processes in development. In mammals, Notch regulates arborization of cortical neurons in vivo (5, 6) and in tissue culture (7,8). In Drosophila, the Notch pathway is required for the elaboration of processes in the CNS in the developing third-instar larva (9) and in the embryo (10, 11). Recently, this work has been extended to the analysis of the developing neuromuscular junction, a structure that serves as an accessible model for CNS plasticity. In addition, a Psn-mediated role for Notch is required in the development of neural projections mediating learned thermotaxis in Caenorhabditis elegans (12). Recently (3), we demonstrated that prolonged disruptions in Notch function produced an early lethality and an impairment in the coordinated neuromuscular activity of flight. Accordingly, because Notch clearly is involved in the regulation of neural ultrastructure during development, we investigated the possibility that Notch is also required for memory consolidation, a process believed to require remodeling of existing neurons in adults (13).Drosophila is an ideal organism for studying genes influencing behavioral phenotypes. Advances in our understanding of learning and memory mechanisms have been achieved through genetic, transgenic, and genomic studies in the fly (14). To investigate Notch function in adults, it is necessary to use conditional reagents to avoid developmental phenotypes that may kill the fly or compromise behavior. We used a Notch temperature-sensitive allele (N ts1 ) (15) and RNA interference (RNAi) derived from an inducible transgene (16), in combination with two independent behavioral assays for memory. We show that short-term memory is not impaired by conditional manipulations of Notch, but that Notch is required in adults for long-term memory. MethodsDrosophila Strai...

A clock gene, period , plays a key role in long-term memory formation in Drosophila

“…3D and Supporting Materials and Methods). Presente et al (29) have also reported that CS males acquires LTM lasting at least 2 days after 5-h conditioning in a similar chamber (12 ϫ 75 mm). Taken together, our result indicates that per mutants are defective in the formation of LTM regardless of the size of conditioning chambers.…”

Cytokine signaling through the JAK/STAT pathway is required for long-term memory in Drosophila

“…Identification of such target genes could be approached by using bioinformatics and/or transcription profiling. Recent profiling studies have identified a number of putative Stat92E target genes in the Drosophila eye disk and hematopoietic system (40,41), some of which include Notch signaling pathway genes that have already been implicated in LTM (42,43). Another mode of action of JAK/STAT signaling in LTM could be through chromatin remodeling.…”

Acute γ-Secretase Inhibition Improves Contextual Fear Conditioning in the Tg2576 Mouse Model of Alzheimer's Disease

“…The acute nature of this effect on cognition, the limited time frame in which inhibition of ␥-secretase is required, and the transgene-specific nature of these effects suggests ␤-amyloid contributes to the cognitive dysfunction in Tg2576 mice. In addition to effects on ␤-amyloid, GSI can affect other proteins, such as Notch (Selkoe, 2001;Presente et al, 2004) and DCC␣ (Parent et al, 2005), implicated in learning and memory. Indeed, loss of presenilin function, a component of ␥-secretase, has been shown to result in impaired memory and synaptic plasticity (Saura et al, 2004).…”