Dscam Mediates Remodeling of Glutamate Receptors in Aplysia during De Novo and Learning-Related Synapse Formation

Howard Hughes Medical Institute, Department of Neuroscience, College of Physicians and Surgeons of Columbia University, 1051 Riverside Drive, New York, NY 10032, USA.
Neuron (Impact Factor: 15.05). 03/2009; 61(4):527-40. DOI: 10.1016/j.neuron.2009.01.010
Source: PubMed

ABSTRACT Transsynaptic interactions between neurons are essential during both developmental and learning-related synaptic growth. We have used Aplysia neuronal cultures to examine the contribution of transsynaptic signals in both types of synapse formation. We find that during de novo synaptogenesis, specific presynaptic innervation is required for the clustering of postsynaptic AMPA-like but not NMDA-like receptors. We further find that the cell adhesion molecule Dscam is involved in these transsynaptic interactions. Inhibition of Dscam either pre- or postsynaptically abolishes the emergence of synaptic transmission and the clustering of AMPA-like receptors. Remodeling of both AMPA-like and NMDA-like receptors also occurs during learning-related synapse formation and again requires the reactivation of Dscam-mediated transsynaptic interactions. Taken together, these findings suggest that learning-induced synapse formation recapitulates, at least in part, aspects of the mechanisms that govern de novo synaptogenesis.

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Available from: Ben S. Huang, Apr 26, 2015
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    • "In the chick retina, DSCAMs, and the closely related Sidekick cell adhesion molecules, are required for the laminar specificity of dendrite arborization in the plexiform layers (Yamagata and Sanes, 2008). In addition to functioning in selfavoidance , vertebrate DSCAMs can also bind the heterologous ligands netrin and draxin and function in axon guidance (Ahmed et al., 2011; Liu et al., 2009; Ly et al., 2008). "
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    ABSTRACT: Cell adhesion molecules (CAMs) provide identifying cues by which neural architecture is sculpted. The Down Syndrome Cell Adhesion Molecule (DSCAM) is required for many neurodevelopmental processes in different species and also has several potential mechanisms of activity, including homophilic adhesion, homophilic repulsion and heterophilic interactions. In the mouse retina, Dscam is expressed in many, but not all neuronal subtypes. Mutations in Dscam cause the fasciculation of dendrites of neighboring homotypic neurons, indicating a role in self-avoidance among cells of a given type, a disruption of the non-random patterning of their cell bodies, and a decrease in developmental cell death in affected cell populations. In order to address how DSCAM facilitates retinal pattering, we developed a conditional allele of Dscam to use alongside existing Dscam mutant mouse strains. Conditional deletion of Dscam reproduces cell spacing, cell number and dendrite arborization defects. Inducible deletion of Dscam and retinal ganglion cell depletion in Brn3b mutant retinas both indicate that these DSCAM-mediated phenotypes can occur independently. In chimeric retinas, in which wild type and Dscam mutant cells are comingled, Dscam mutant cells entangle adjacent wild type cells of the same type, as if both cells were lacking Dscam, consistent with DSCAM-dependent cell spacing and neurite arborization being mediated through homophilic binding cell-to-cell. Deletion of Dscam in specific cell types causes cell-type-autonomous cell body spacing defects, indicating that DSCAM mediates arborization and spacing by acting within given cell types. We also examine the cell autonomy of DSCAM in laminar stratification and find that laminar disorganization can be caused in a non-cell autonomous fashion. Finally, we find Dscam dosage-dependent defects in developmental cell death and amacrine cell spacing, relevant to the increased cell death and other disorders observed in Down syndrome mouse models and human patients, in which Dscam is present in three copies.
    Developmental Biology 10/2011; 361(2):326-37. DOI:10.1016/j.ydbio.2011.10.028 · 3.55 Impact Factor
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    • "What are the downstream cellular consequences of continued PKM Apl III activity that serve to maintain stable synaptic facilitation in Aplysia? One possibility is that ongoing PKM Apl III activity maintains learning-induced changes in neuronal structure (see Liu et al., 2009). Both LTS and LTF are accompanied by the growth of new synapses, and this growth involves both presynaptic and postsynaptic structural changes (Bailey and Chen, 1983, 1988b; Bailey and Chen, 1988a; Glanzman et al., 1990; Wainwright et al., 2002). "
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    ABSTRACT: How the brain maintains long-term memories is one of the major outstanding questions in modern neuroscience. Evidence from mammalian studies indicates that activity of a protein kinase C (PKC) isoform, protein kinase Mζ (PKMζ), plays a critical role in the maintenance of long-term memory. But the range of memories whose persistence depends on PKMζ, and the mechanisms that underlie the effect of PKMζ on long-term memory, remain obscure. Recently, a PKM isoform, known as PKM Apl III, was cloned from the nervous system of Aplysia. Here, we tested whether PKM Apl III plays a critical role in long-term memory maintenance in Aplysia. Intrahemocoel injections of the pseudosubstrate inhibitory peptide ZIP (ζ inhibitory peptide) or the PKC inhibitor chelerythrine erased the memory for long-term sensitization (LTS) of the siphon-withdrawal reflex (SWR) as late as 7 d after training. In addition, both PKM inhibitors disrupted the maintenance of long-term (≥ 24 h) facilitation (LTF) of the sensorimotor synapse, a form of synaptic plasticity previously shown to mediate LTS of the SWR. Together with previous results (Bougie et al., 2009), our results support the idea that long-term memory in Aplysia is maintained via a positive-feedback loop involving PKM Apl III-dependent protein phosphorylation. The present data extend the known role of PKM in memory maintenance to a simple and well studied type of long-term learning. Furthermore, the demonstration that PKM activity underlies the persistence of LTF of the Aplysia sensorimotor synapse, a form of synaptic plasticity amenable to rigorous cellular and molecular analyses, should facilitate efforts to understand how PKM activity maintains memory.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 04/2011; 31(17):6421-31. DOI:10.1523/JNEUROSCI.4744-10.2011 · 6.34 Impact Factor
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    • "These results support the idea that the intermediate-term stage is the first stage to involve both pre-and postsynaptic molecular mechanisms. Those mechanisms could serve as early steps in a program leading to synaptic growth during long-term facilitation, which also involves both pre-and postsynaptic mechanisms coordinated by transynaptic signaling (Trudeau and Castellucci 1995; Kandel 2001; Sherff and Carew 2004; Cai et al. 2008; Li et al. 2009; Wang et al. 2009). That idea in turn raises a number of new questions about the stages and their interrelations . "
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    ABSTRACT: Whereas short-term plasticity involves covalent modifications that are generally restricted to either presynaptic or postsynaptic structures, long-term plasticity involves the growth of new synapses, which by its nature involves both pre- and postsynaptic alterations. In addition, an intermediate-term stage of plasticity has been identified that might form a bridge between short- and long-term plasticity. Consistent with that idea, although short-term term behavioral sensitization in Aplysia involves presynaptic mechanisms, intermediate-term sensitization involves both pre- and postsynaptic mechanisms. However, it has not been known whether that is also true of facilitation in vitro, where a more detailed analysis of the mechanisms involved in the different stages and their interrelations is feasible. To address those questions, we have examined pre- and postsynaptic mechanisms of short- and intermediate-term facilitation at Aplysia sensory-motor neuron synapses in isolated cell culture. Whereas short-term facilitation by 1-min 5-HT involves presynaptic PKA and CamKII, intermediate-term facilitation by 10-min 5-HT involves presynaptic PKC and postsynaptic Ca(2+) and CamKII, as well as both pre- and postsynaptic protein synthesis. These results support the idea that the intermediate-term stage is the first to involve both pre- and postsynaptic molecular mechanisms, which could in turn serve as some of the initial steps in a cascade leading to synaptic growth during long-term plasticity.
    Learning & memory (Cold Spring Harbor, N.Y.) 01/2011; 18(2):96-102. DOI:10.1101/lm.1949711 · 3.66 Impact Factor
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