ABSTRACT
Most neurons possess a single, nonmotile cilium that projects out from the cell surface. These microtubule-based organelles are important in brain development and neurogenesis; however, their function in mature neurons is unknown. Cilia express a complement of proteins distinct from other neuronal compartments, one of which is the somatostatin receptor subtype SST(3). We show here that SST(3) is critical for object recognition memory in mice. sst3 knock-out mice are severely impaired in discriminating novel objects, whereas they retain normal memory for object location. Further, systemic injection of an SST(3) antagonist (ACQ090) disrupts recall of familiar objects in wild-type mice. To examine mechanisms of SST(3), we tested synaptic plasticity in CA1 hippocampus. Electrically evoked long-term potentiation (LTP) was normal in sst3 knock-out mice, while adenylyl cyclase/cAMP-mediated LTP was impaired. The SST(3) antagonist also disrupted cAMP-mediated LTP. Basal cAMP levels in hippocampal lysate were reduced in sst3 knock-out mice compared with wild-type mice, while the forskolin-induced increase in cAMP levels was normal. The SST(3) antagonist inhibited forskolin-stimulated cAMP increases, whereas the SST(3) agonist L-796,778 increased basal cAMP levels in hippocampal slices but not hippocampal lysate. Our results show that somatostatin signaling in neuronal cilia is critical for recognition memory and suggest that the cAMP pathway is a conserved signaling motif in cilia. Neuronal cilia therefore represent a novel nonsynaptic compartment crucial for signaling involved in a specific form of synaptic plasticity and in novelty detection.
Subject(s)
Locomotion/physiology , Neurons/cytology , Recognition, Psychology/physiology , Signal Transduction/physiology , Somatostatin/metabolism , 1-Methyl-3-isobutylxanthine/pharmacology , Action Potentials/drug effects , Action Potentials/genetics , Adenylyl Cyclases/metabolism , Amides/pharmacology , Animals , Behavior, Animal , Bicuculline/analogs & derivatives , Bicuculline/pharmacology , Biophysics/methods , CA1 Region, Hippocampal/cytology , Cilia/metabolism , Colforsin/pharmacology , Cyclic AMP/metabolism , Discrimination, Psychological , Electric Stimulation/methods , Female , GABA Antagonists/pharmacology , In Vitro Techniques , Isoquinolines/pharmacology , Locomotion/drug effects , Locomotion/genetics , Long-Term Potentiation/drug effects , Long-Term Potentiation/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Neuropsychological Tests , Nitrobenzenes/pharmacology , Phosphodiesterase Inhibitors/pharmacology , Receptors, Somatostatin/agonists , Receptors, Somatostatin/antagonists & inhibitors , Receptors, Somatostatin/deficiency , Receptors, Somatostatin/metabolism , Recognition, Psychology/drug effects , Signal Transduction/drug effectsABSTRACT
This study presents the first characterization of a WD40 repeat-containing myosin identified in the apicomplexan parasite Gregarina polymorpha. This 222.7 kDa myosin, GpMyoF, contains a canonical myosin motor domain, a neck domain with 6 IQ motifs, a tail domain containing short regions of predicted coiled-coil structure, and, most notably, multiple WD40 repeats at the C-terminus. In other proteins such repeats assemble into a beta-propeller structure implicated in mediating protein-protein interactions. Confocal microscopy suggests that GpMyoF is localized to the annular myonemes that gird the parasite cortex. Extraction studies indicate that this myosin shows an unusually tight association with the cytoskeletal fraction and can be solubilized only by treatment with high pH (11.5) or the anionic detergent sarkosyl. This novel myosin and its homologs, which have been identified in several related genera, appear to be unique to the Apicomplexa and represent the only myosins known to contain the WD40 domain. The function of this myosin in G. polymorpha or any of the other apicomplexan parasites remains uncertain.
