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106 Publications

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    12/31/07 | Huntingtin-interacting protein 14, a palmitoyl transferase required for exocytosis and targeting of CSP to synaptic vesicles.
    Ohyama T, Verstreken P, Ly CV, Rosenmund T, Rajan A, Tien A, Haueter C, Schulze KL, Bellen HJ
    The Journal of Cell Biology. 2007 Dec 31;179(7):1481-96. doi: 10.1083/jcb.200710061

    Posttranslational modification through palmitoylation regulates protein localization and function. In this study, we identify a role for the Drosophila melanogaster palmitoyl transferase Huntingtin-interacting protein 14 (HIP14) in neurotransmitter release. hip14 mutants show exocytic defects at low frequency stimulation and a nearly complete loss of synaptic transmission at higher temperature. Interestingly, two exocytic components known to be palmitoylated, cysteine string protein (CSP) and SNAP25, are severely mislocalized at hip14 mutant synapses. Complementary DNA rescue and localization experiments indicate that HIP14 is required solely in the nervous system and is essential for presynaptic function. Biochemical studies indicate that HIP14 palmitoylates CSP and that CSP is not palmitoylated in hip14 mutants. Furthermore, the hip14 exocytic defects can be suppressed by targeting CSP to synaptic vesicles using a chimeric protein approach. Our data indicate that HIP14 controls neurotransmitter release by regulating the trafficking of CSP to synapses.

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    12/28/07 | Function of the Drosophila CPEB protein Orb2 in long-term courtship memory.
    Keleman K, Krüttner S, Alenius M, Dickson BJ
    Nature Neuroscience. 2007 Dec 28;10(12):1587-93. doi: 10.1038/nn1996

    Both long-term behavioral memory and synaptic plasticity require protein synthesis, some of which may occur locally at specific synapses. Cytoplasmic polyadenylation element-binding (CPEB) proteins are thought to contribute to the local protein synthesis that underlies long-term changes in synaptic efficacy, but a role has not been established for them in the formation of long-term behavioral memory. We found that the Drosophila melanogaster CPEB protein Orb2 is acutely required for long-term conditioning of male courtship behavior. Deletion of the N-terminal glutamine-rich region of Orb2 resulted in flies that were impaired in their ability to form long-term, but not short-term, memory. Memory was restored by expressing Orb2 selectively in fruitless (fru)-positive gamma neurons of the mushroom bodies and by providing Orb2 function in mushroom bodies only during and shortly after training. Our data thus demonstrate that a CPEB protein is important in long-term memory and map the molecular, spatial and temporal requirements for its function in memory formation.

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    12/20/07 | HCN1 channels constrain synaptically evoked Ca2+ spikes in distal dendrites of CA1 pyramidal neurons.
    Tsay D, Dudman JT, Siegelbaum SA
    Neuron. 2007 Dec 20;56(6):1076-89. doi: 10.1016/j.neuron.2007.11.015

    HCN1 hyperpolarization-activated cation channels act as an inhibitory constraint of both spatial learning and synaptic integration and long-term plasticity in the distal dendrites of hippocampal CA1 pyramidal neurons. However, as HCN1 channels provide an excitatory current, the mechanism of their inhibitory action remains unclear. Here we report that HCN1 channels also constrain CA1 distal dendritic Ca2+ spikes, which have been implicated in the induction of LTP at distal excitatory synapses. Our experimental and computational results indicate that HCN1 channels provide both an active shunt conductance that decreases the temporal integration of distal EPSPs and a tonic depolarizing current that increases resting inactivation of T-type and N-type voltage-gated Ca2+ channels, which contribute to the Ca2+ spikes. This dual mechanism may provide a general means by which HCN channels regulate dendritic excitability.

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    Svoboda Lab
    12/20/07 | Locally dynamic synaptic learning rules in pyramidal neuron dendrites.
    Harvey CD, Svoboda K
    Nature. 2007 Dec 20;450(7173):1195-200. doi: 10.1038/nature06416

    Long-term potentiation (LTP) of synaptic transmission underlies aspects of learning and memory. LTP is input-specific at the level of individual synapses, but neural network models predict interactions between plasticity at nearby synapses. Here we show in mouse hippocampal pyramidal cells that LTP at individual synapses reduces the threshold for potentiation at neighbouring synapses. After input-specific LTP induction by two-photon glutamate uncaging or by synaptic stimulation, subthreshold stimuli, which by themselves were too weak to trigger LTP, caused robust LTP and spine enlargement at neighbouring spines. Furthermore, LTP induction broadened the presynaptic-postsynaptic spike interval for spike-timing-dependent LTP within a dendritic neighbourhood. The reduction in the threshold for LTP induction lasted approximately 10 min and spread over approximately 10 microm of dendrite. These local interactions between neighbouring synapses support clustered plasticity models of memory storage and could allow for the binding of behaviourally linked information on the same dendritic branch.

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    12/18/07 | Dual-color superresolution imaging of genetically expressed probes within individual adhesion complexes. (With commentary)
    Shroff H, Galbraith CG, Galbraith JA, White H, Gillette J, Olenych S, Davidson MW, Betzig E
    Proceedings of the National Academy of Sciences of the United States of America. 2007 Dec 18;104:20308-13. doi: 10.1073/pnas.0710517105

    Accurate determination of the relative positions of proteins within localized regions of the cell is essential for understanding their biological function. Although fluorescent fusion proteins are targeted with molecular precision, the position of these genetically expressed reporters is usually known only to the resolution of conventional optics ( approximately 200 nm). Here, we report the use of two-color photoactivated localization microscopy (PALM) to determine the ultrastructural relationship between different proteins fused to spectrally distinct photoactivatable fluorescent proteins (PA-FPs). The nonperturbative incorporation of these endogenous tags facilitates an imaging resolution in whole, fixed cells of approximately 20-30 nm at acquisition times of 5-30 min. We apply the technique to image different pairs of proteins assembled in adhesion complexes, the central attachment points between the cytoskeleton and the substrate in migrating cells. For several pairs, we find that proteins that seem colocalized when viewed by conventional optics are resolved as distinct interlocking nano-aggregates when imaged via PALM. The simplicity, minimal invasiveness, resolution, and speed of the technique all suggest its potential to directly visualize molecular interactions within cellular structures at the nanometer scale.

    Commentary: Identifies the photoactivatable fluorescent proteins (PA-FPs) Dronpa and PS-CFP2 as green partners to orange-red PA-FPs such as Kaede and Eos for dual color PALM imaging. Very low crosstalk is demonstrated between the two color channels. Furthermore, since the probes are genetically expressed, they are closely bound to their target proteins and exhibit zero non-specific background. All these properties are essential to unambiguously identify regions of co-localization or separate compartmentalization at the nanoscale, as demonstrated in the examples here.

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    12/06/07 | A role for synaptic inputs at distal dendrites: instructive signals for hippocampal long-term plasticity.
    Dudman JT, Tsay D, Siegelbaum SA
    Neuron. 2007 Dec 6;56(5):866-79. doi: 10.1016/j.neuron.2007.10.020

    Synaptic potentials originating at distal dendritic locations are severely attenuated when they reach the soma and, thus, are poor at driving somatic spikes. Nonetheless, distal inputs convey essential information, suggesting that such inputs may be important for compartmentalized dendritic signaling. Here we report a new plasticity rule in which stimulation of distal perforant path inputs to hippocampal CA1 pyramidal neurons induces long-term potentiation at the CA1 proximal Schaffer collateral synapses when the two inputs are paired at a precise interval. This subthreshold form of heterosynaptic plasticity occurs in the absence of somatic spiking but requires activation of both NMDA receptors and IP(3) receptor-dependent release of Ca(2+) from internal stores. Our results suggest that direct sensory information arriving at distal CA1 synapses through the perforant path provide compartmentalized, instructive signals that assess the saliency of mnemonic information propagated through the hippocampal circuit to proximal synapses.

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    12/03/07 | Coincidence detection of place and temporal context in a network model of spiking hippocampal neurons.
    Katz Y, Kath WL, Spruston N, Hasselmo ME
    PLoS Computational Biology. 2007 Dec;3(12):e234. doi: 10.1371/journal.pcbi.0030234

    Recent advances in single-neuron biophysics have enhanced our understanding of information processing on the cellular level, but how the detailed properties of individual neurons give rise to large-scale behavior remains unclear. Here, we present a model of the hippocampal network based on observed biophysical properties of hippocampal and entorhinal cortical neurons. We assembled our model to simulate spatial alternation, a task that requires memory of the previous path through the environment for correct selection of the current path to a reward site. The convergence of inputs from entorhinal cortex and hippocampal region CA3 onto CA1 pyramidal cells make them potentially important for integrating information about place and temporal context on the network level. Our model shows how place and temporal context information might be combined in CA1 pyramidal neurons to give rise to splitter cells, which fire selectively based on a combination of place and temporal context. The model leads to a number of experimentally testable predictions that may lead to a better understanding of the biophysical basis of information processing in the hippocampus.

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    Eddy/Rivas Lab
    12/01/07 | Identification of differentially expressed small non-coding RNAs in the legume endosymbiont Sinorhizobium meliloti by comparative genomics.
    del Val C, Rivas E, Torres-Quesada O, Toro N, Jiménez-Zurdo JI
    Molecular Microbiology. 2007 Dec;66(5):1080-91. doi: 10.1111/j.1365-2958.2007.05978.x

    Bacterial small non-coding RNAs (sRNAs) are being recognized as novel widespread regulators of gene expression in response to environmental signals. Here, we present the first search for sRNA-encoding genes in the nitrogen-fixing endosymbiont Sinorhizobium meliloti, performed by a genome-wide computational analysis of its intergenic regions. Comparative sequence data from eight related alpha-proteobacteria were obtained, and the interspecies pairwise alignments were scored with the programs eQRNA and RNAz as complementary predictive tools to identify conserved and stable secondary structures corresponding to putative non-coding RNAs. Northern experiments confirmed that eight of the predicted loci, selected among the original 32 candidates as most probable sRNA genes, expressed small transcripts. This result supports the combined use of eQRNA and RNAz as a robust strategy to identify novel sRNAs in bacteria. Furthermore, seven of the transcripts accumulated differentially in free-living and symbiotic conditions. Experimental mapping of the 5’-ends of the detected transcripts revealed that their encoding genes are organized in autonomous transcription units with recognizable promoter and, in most cases, termination signatures. These findings suggest novel regulatory functions for sRNAs related to the interactions of alpha-proteobacteria with their eukaryotic hosts.

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    12/01/07 | Internal and external constraints in the evolution of morphological allometries in a butterfly.
    Frankino WA, Zwaan BJ, Stern DL, Brakefield PM
    Evolution. 2007 Dec;61(12):2958-70. doi: 10.1111/j.1558-5646.2007.00249.x

    Much diversity in animal morphology results from variation in the relative size of morphological traits. The scaling relationships, or allometries, that describe relative trait size can vary greatly in both intercept and slope among species or other animal groups. Yet within such groups, individuals typically exhibit low variation in relative trait size. This pattern of high intra- and low intergroup variation may result from natural selection for particular allometries, from developmental constraints restricting differential growth among traits, or both. Here we explore the relative roles of short-term developmental constraints and natural selection in the evolution of the intercept of the allometry between the forewing and hindwing of a butterfly. First, despite a strong genetic correlation between these two traits, we show that artificial selection perpendicular to the forewing-hindwing scaling relationship results in rapid evolution of the allometry intercept. This demonstrates an absence of developmental constraints limiting intercept evolution for this scaling relationship. Mating experiments in a natural environment revealed strong stabilizing selection favoring males with the wild-type allometry intercept over those with derived intercepts. Our results demonstrate that evolution of this component of the forewing-hindwing allometry is not limited by developmental constraints in the short term and that natural selection on allometry intercepts can be powerful.

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    12/01/07 | Olfactory coding with all-or-nothing glomeruli.
    Koulakov A, Gelperin A, Rinberg D
    Journal of Neurophysiology. 2007 Dec;98(6):3134-42. doi: 10.1523/JNEUROSCI.3613-08.2008

    We present a model for olfactory coding based on spatial representation of glomerular responses. In this model distinct odorants activate specific subsets of glomeruli, dependent on the odorant’s chemical identity and concentration. The glomerular response specificities are understood statistically, based on experimentally measured distributions of activation thresholds. A simple version of the model, in which glomerular responses are binary (the all-or-nothing model), allows us to account quantitatively for the following results of human/rodent olfactory psychophysics: 1) just noticeable differences in the perceived concentration of a single odor (Weber ratios) are as low as dC/C approximately 0.04; 2) the number of simultaneously perceived odors can be as high as 12; and 3) extensive lesions of the olfactory bulb do not lead to significant changes in detection or discrimination thresholds. We conclude that a combinatorial code based on a binary glomerular response is sufficient to account for several important features of the discrimination capacity of the mammalian olfactory system.

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