Ca21 Signaling via the Neuronal Calcium Sensor-1 Regulates Associative Learning and Memory in C. elegans

orthologs identified in yeast, Drosophila, C. elegans, avian birds, rodents, and humans (Nef, 1996). Its amino acid sequence is 100% conserved among vertebrates and shows only 25% divergence with C. elegans or 28% with yeast (De Castro et al., 1995). NCS-1 is neuron Indeed, calmodulin-dependent targets such as 3Ј:5Ј-cyclic nucleotide phosphodiesterase, calcineurin, Japan 4 Howard Hughes Medical Institute nitric oxide synthase enzymes (in vitro), or the Parame-cium calmodulin-dependent potassium channel (in vivo) are directly activated by NCS-1 (Schaad et al., 1996). Moreover, overexpression of NCS-1 in the mouse hippo-San Francisco, California 94143 campus increases long-term potentiation (LTP) (P. N. et al., unpublished data), and overexpression of frequenin, the Drosophila ortholog of NCS-1, causes a chronic fa-Summary cilitation of transmitter release at the neuromuscular junction of flies and frogs through unknown mechanisms On a radial temperature gradient, C. elegans worms Olafsson et migrate, after conditioning with food, toward their cul-al., 1995). Importantly, the neuronal role of ncs genes tivation temperature and move along this isotherm. in vivo has not been characterized by loss-of-function This experience-dependent behavior is called isother-genetics in eukaryotes. To investigate the role of NCS-1 mal tracking (IT). Here we show that the neuron-spe-as a regulator of neuronal activity in vivo, we chose C. cific calcium sensor-1 (NCS-1) is essential for optimal elegans as a model organism due to its simple nervous IT. ncs-1 knockout animals show major defects in IT system and well-described neuronal circuitry with the behavior, although their chemotactic, locomotor, and ability to respond to diverse environmental stimuli such thermal avoidance behaviors are normal. The knock-as touch, smell, taste, or temperature. out phenotype can be rescued by reintroducing wild-type NCS-1 into the AIY interneuron, a key component Results of the thermotaxis network. A loss-of-function form of NCS-1 incapable of binding calcium does not re-The Ce-ncs-1 gene, located on the left arm of chromo-store IT, whereas NCS-1 overexpression enhances IT some X, encodes Ce-NCS-1, a small acidic protein com-performance levels, accelerates learning (faster ac-posed of 192 amino acids (molecular mass of 22 kDa) quisition), and produces a memory with slower extinc-that binds three calcium ions via four putative EF-hands tion. Thus, proper calcium signaling via NCS-1 defines (De Castro et al., 1995). Cellular distribution of Ce-NCS-1 a novel pathway essential for associative learning and was determined by light and immunofluorescence mi-memory. croscopy studies using a transgenic line (XA411) expressing the green fluorescent protein (GFP) under the Introduction …