Publications by authors named "Timothy J Mosca"

16 Publications

  • Page 1 of 1

Conservation and Innovation: Versatile Roles for LRP4 in Nervous System Development.

J Dev Biol 2021 Mar 14;9(1). Epub 2021 Mar 14.

Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107, USA.

As the nervous system develops, connections between neurons must form to enable efficient communication. This complex process of synaptic development requires the coordination of a series of intricate mechanisms between partner neurons to ensure pre- and postsynaptic differentiation. Many of these mechanisms employ transsynaptic signaling via essential secreted factors and cell surface receptors to promote each step of synaptic development. One such cell surface receptor, LRP4, has emerged as a synaptic organizer, playing a critical role in conveying extracellular signals to initiate diverse intracellular events during development. To date, LRP4 is largely known for its role in development of the mammalian neuromuscular junction, where it functions as a receptor for the synaptogenic signal Agrin to regulate synapse development. Recently however, LRP4 has emerged as a synapse organizer in the brain, where new functions for the protein continue to arise, adding further complexity to its already versatile roles. Additional findings indicate that LRP4 plays a role in disorders of the nervous system, including myasthenia gravis, amyotrophic lateral sclerosis, and Alzheimer's disease, demonstrating the need for further study to understand disease etiology. This review will highlight our current knowledge of how LRP4 functions in the nervous system, focusing on the diverse developmental roles and different modes this essential cell surface protein uses to ensure the formation of robust synaptic connections.
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http://dx.doi.org/10.3390/jdb9010009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006230PMC
March 2021

Zinc Finger RNA-Binding Protein Zn72D Regulates ADAR-Mediated RNA Editing in Neurons.

Cell Rep 2020 05;31(7):107654

Department of Genetics, Stanford University, Stanford, CA 94305, USA. Electronic address:

Adenosine-to-inosine RNA editing, catalyzed by adenosine deaminase acting on RNA (ADAR) enzymes, alters RNA sequences from those encoded by DNA. These editing events are dynamically regulated, but few trans regulators of ADARs are known in vivo. Here, we screen RNA-binding proteins for roles in editing regulation with knockdown experiments in the Drosophila brain. We identify zinc-finger protein at 72D (Zn72D) as a regulator of editing levels at a majority of editing sites in the brain. Zn72D both regulates ADAR protein levels and interacts with ADAR in an RNA-dependent fashion, and similar to ADAR, Zn72D is necessary to maintain proper neuromuscular junction architecture and fly mobility. Furthermore, Zn72D's regulatory role in RNA editing is conserved because the mammalian homolog of Zn72D, Zfr, regulates editing in mouse primary neurons. The broad and conserved regulation of ADAR editing by Zn72D in neurons sustains critically important editing events.
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http://dx.doi.org/10.1016/j.celrep.2020.107654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306179PMC
May 2020

The Tenets of Teneurin: Conserved Mechanisms Regulate Diverse Developmental Processes in the Nervous System.

Front Neurosci 2019 30;13:27. Epub 2019 Jan 30.

Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA, United States.

To successfully integrate a neuron into a circuit, a myriad of developmental events must occur correctly and in the correct order. Neurons must be born and grow out toward a destination, responding to guidance cues to direct their path. Once arrived, each neuron must segregate to the correct sub-region before sorting through a milieu of incorrect partners to identify the correct partner with which they can connect. Finally, the neuron must make a synaptic connection with their correct partner; a connection that needs to be broadly maintained throughout the life of the animal while remaining responsive to modes of plasticity and pruning. Though many intricate molecular mechanisms have been discovered to regulate each step, recent work showed that a single family of proteins, the Teneurins, regulates a host of these developmental steps in - an example of biological adaptive reuse. Teneurins first influence axon guidance during early development. Once neurons arrive in their target regions, Teneurins enable partner matching and synapse formation in both the central and peripheral nervous systems. Despite these diverse processes and systems, the Teneurins use conserved mechanisms to achieve these goals, as defined by three tenets: (1) transsynaptic interactions with each other, (2) membrane stabilization via an interaction with and regulation of the cytoskeleton, and (3) a role for presynaptic Ten-a in regulating synaptic function. These processes are further distinguished by (1) the nature of the transsynaptic interaction - homophilic interactions (between the same Teneurins) to engage partner matching and heterophilic interactions (between different Teneurins) to enable synaptic connectivity and the proper apposition of pre- and postsynaptic sites and (2) the location of cytoskeletal regulation (presynaptic cytoskeletal regulation in the CNS and postsynaptic regulation of the cytoskeleton at the NMJ). Thus, both the roles and the mechanisms governing them are conserved across processes and synapses. Here, we will highlight the contributions of synaptic biology to our understanding of the Teneurins, discuss the mechanistic conservation that allows the Teneurins to achieve common neurodevelopmental goals, and present new data in support of these points. Finally, we will posit the next steps for understanding how this remarkably versatile family of proteins functions to control multiple distinct events in the creation of a nervous system.
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http://dx.doi.org/10.3389/fnins.2019.00027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363694PMC
January 2019

Rabies screen reveals GPe control of cocaine-triggered plasticity.

Nature 2017 09 13;549(7672):345-350. Epub 2017 Sep 13.

Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California 94305, USA.

Identification of neural circuit changes that contribute to behavioural plasticity has routinely been conducted on candidate circuits that were preselected on the basis of previous results. Here we present an unbiased method for identifying experience-triggered circuit-level changes in neuronal ensembles in mice. Using rabies virus monosynaptic tracing, we mapped cocaine-induced global changes in inputs onto neurons in the ventral tegmental area. Cocaine increased rabies-labelled inputs from the globus pallidus externus (GPe), a basal ganglia nucleus not previously known to participate in behavioural plasticity triggered by drugs of abuse. We demonstrated that cocaine increased GPe neuron activity, which accounted for the increase in GPe labelling. Inhibition of GPe activity revealed that it contributes to two forms of cocaine-triggered behavioural plasticity, at least in part by disinhibiting dopamine neurons in the ventral tegmental area. These results suggest that rabies-based unbiased screening of changes in input populations can identify previously unappreciated circuit elements that critically support behavioural adaptations.
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http://dx.doi.org/10.1038/nature23888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6069680PMC
September 2017

Drosophila mutants lacking octopamine exhibit impairment in aversive olfactory associative learning (Commentary on Iliadi et al. (2017)).

Authors:
Timothy J Mosca

Eur J Neurosci 2017 09 2;46(5):2078-2079. Epub 2017 Aug 2.

Department of Neuroscience and Vickie and Jack Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, PA, 19107, USA.

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http://dx.doi.org/10.1111/ejn.13651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5683077PMC
September 2017

Presynaptic LRP4 promotes synapse number and function of excitatory CNS neurons.

Elife 2017 06 13;6. Epub 2017 Jun 13.

Department of Biology, Howard Hughes Medical Institute, Stanford University, Stanford, United States.

Precise coordination of synaptic connections ensures proper information flow within circuits. The activity of presynaptic organizing molecules signaling to downstream pathways is essential for such coordination, though such entities remain incompletely known. We show that LRP4, a conserved transmembrane protein known for its postsynaptic roles, functions presynaptically as an organizing molecule. In the brain, LRP4 localizes to the nerve terminals at or near active zones. Loss of presynaptic LRP4 reduces excitatory (not inhibitory) synapse number, impairs active zone architecture, and abolishes olfactory attraction - the latter of which can be suppressed by reducing presynaptic GABA receptors. LRP4 overexpression increases synapse number in excitatory and inhibitory neurons, suggesting an instructive role and a common downstream synapse addition pathway. Mechanistically, LRP4 functions via the conserved kinase SRPK79D to ensure normal synapse number and behavior. This highlights a presynaptic function for LRP4, enabling deeper understanding of how synapse organization is coordinated.
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http://dx.doi.org/10.7554/eLife.27347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5469616PMC
June 2017

The Strip-Hippo Pathway Regulates Synaptic Terminal Formation by Modulating Actin Organization at the Drosophila Neuromuscular Synapses.

Cell Rep 2016 08 18;16(9):2289-97. Epub 2016 Aug 18.

Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; AMED-CREST, Japan Agency for Medical Research and Development, 20F Yomiuri Shimbun Building 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan; Department of Biological Science, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan. Electronic address:

Synapse formation requires the precise coordination of axon elongation, cytoskeletal stability, and diverse modes of cell signaling. The underlying mechanisms of this interplay, however, remain unclear. Here, we demonstrate that Strip, a component of the striatin-interacting phosphatase and kinase (STRIPAK) complex that regulates these processes, is required to ensure the proper development of synaptic boutons at the Drosophila neuromuscular junction. In doing so, Strip negatively regulates the activity of the Hippo (Hpo) pathway, an evolutionarily conserved regulator of organ size whose role in synapse formation is currently unappreciated. Strip functions genetically with Enabled, an actin assembly/elongation factor and the presumptive downstream target of Hpo signaling, to modulate local actin organization at synaptic termini. This regulation occurs independently of the transcriptional co-activator Yorkie, the canonical downstream target of the Hpo pathway. Our study identifies a previously unanticipated role of the Strip-Hippo pathway in synaptic development, linking cell signaling to actin organization.
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http://dx.doi.org/10.1016/j.celrep.2016.07.066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5023852PMC
August 2016

On the Teneurin track: a new synaptic organization molecule emerges.

Authors:
Timothy J Mosca

Front Cell Neurosci 2015 27;9:204. Epub 2015 May 27.

Department of Biology, Stanford University Stanford, CA, USA.

To achieve proper synaptic development and function, coordinated signals must pass between the pre- and postsynaptic membranes. Such transsynaptic signals can be comprised of receptors and secreted ligands, membrane associated receptors, and also pairs of synaptic cell adhesion molecules. A critical open question bridging neuroscience, developmental biology, and cell biology involves identifying those signals and elucidating how they function. Recent work in Drosophila and vertebrate systems has implicated a family of proteins, the Teneurins, as a new transsynaptic signal in both the peripheral and central nervous systems. The Teneurins have established roles in neuronal wiring, but studies now show their involvement in regulating synaptic connections between neurons and bridging the synaptic membrane and the cytoskeleton. This review will examine the Teneurins as synaptic cell adhesion molecules, explore how they regulate synaptic organization, and consider how some consequences of human Teneurin mutations may have synaptopathic origins.
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http://dx.doi.org/10.3389/fncel.2015.00204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4444827PMC
June 2015

Synaptic organization of the Drosophila antennal lobe and its regulation by the Teneurins.

Elife 2014 Oct 13;3:e03726. Epub 2014 Oct 13.

Department of Biology, Howard Hughes Medical Institute, Stanford University, Stanford, United States.

Understanding information flow through neuronal circuits requires knowledge of their synaptic organization. In this study, we utilized fluorescent pre- and postsynaptic markers to map synaptic organization in the Drosophila antennal lobe, the first olfactory processing center. Olfactory receptor neurons (ORNs) produce a constant synaptic density across different glomeruli. Each ORN within a class contributes nearly identical active zone number. Active zones from ORNs, projection neurons (PNs), and local interneurons have distinct subglomerular and subcellular distributions. The correct number of ORN active zones and PN acetylcholine receptor clusters requires the Teneurins, conserved transmembrane proteins involved in neuromuscular synapse organization and synaptic partner matching. Ten-a acts in ORNs to organize presynaptic active zones via the spectrin cytoskeleton. Ten-m acts in PNs autonomously to regulate acetylcholine receptor cluster number and transsynaptically to regulate ORN active zone number. These studies advanced our ability to assess synaptic architecture in complex CNS circuits and their underlying molecular mechanisms.
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http://dx.doi.org/10.7554/eLife.03726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4194450PMC
October 2014

Plum, an immunoglobulin superfamily protein, regulates axon pruning by facilitating TGF-β signaling.

Neuron 2013 May;78(3):456-68

Department of Biology, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94303, USA.

Axon pruning during development is essential for proper wiring of the mature nervous system, but its regulation remains poorly understood. We have identified an immunoglobulin superfamily (IgSF) transmembrane protein, Plum, that is cell autonomously required for axon pruning of mushroom body (MB) γ neurons and for ectopic synapse refinement at the developing neuromuscular junction in Drosophila. Plum promotes MB γ neuron axon pruning by regulating the expression of Ecdysone Receptor-B1, a key initiator of axon pruning. Genetic analyses indicate that Plum acts to facilitate signaling of Myoglianin, a glial-derived TGF-β, on MB γ neurons upstream of the type-I TGF-β receptor Baboon. Myoglianin, Baboon, and Ecdysone Receptor-B1 are also required for neuromuscular junction ectopic synapse refinement. Our study highlights both IgSF proteins and TGF-β facilitation as key promoters of developmental axon elimination and demonstrates a mechanistic conservation between MB axon pruning during metamorphosis and the refinement of ectopic larval neuromuscular connections.
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http://dx.doi.org/10.1016/j.neuron.2013.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3706783PMC
May 2013

Trans-synaptic Teneurin signalling in neuromuscular synapse organization and target choice.

Nature 2012 Mar 18;484(7393):237-41. Epub 2012 Mar 18.

Department of Biology, Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA.

Synapse assembly requires trans-synaptic signals between the pre- and postsynapse, but our understanding of the essential organizational molecules involved in this process remains incomplete. Teneurin proteins are conserved, epidermal growth factor (EGF)-repeat-containing transmembrane proteins with large extracellular domains. Here we show that two Drosophila Teneurins, Ten-m and Ten-a, are required for neuromuscular synapse organization and target selection. Ten-a is presynaptic whereas Ten-m is mostly postsynaptic; neuronal Ten-a and muscle Ten-m form a complex in vivo. Pre- or postsynaptic Teneurin perturbations cause severe synapse loss and impair many facets of organization trans-synaptically and cell autonomously. These include defects in active zone apposition, release sites, membrane and vesicle organization, and synaptic transmission. Moreover, the presynaptic microtubule and postsynaptic spectrin cytoskeletons are severely disrupted, suggesting a mechanism whereby Teneurins organize the cytoskeleton, which in turn affects other aspects of synapse development. Supporting this, Ten-m physically interacts with α-Spectrin. Genetic analyses of teneurin and neuroligin reveal that they have differential roles that synergize to promote synapse assembly. Finally, at elevated endogenous levels, Ten-m regulates target selection between specific motor neurons and muscles. Our study identifies the Teneurins as a key bi-directional trans-synaptic signal involved in general synapse organization, and demonstrates that proteins such as these can also regulate target selection.
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http://dx.doi.org/10.1038/nature10923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3326183PMC
March 2012

Teneurins instruct synaptic partner matching in an olfactory map.

Nature 2012 Mar 18;484(7393):201-7. Epub 2012 Mar 18.

Department of Biology, Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA.

Neurons are interconnected with extraordinary precision to assemble a functional nervous system. Compared to axon guidance, far less is understood about how individual pre- and postsynaptic partners are matched. To ensure the proper relay of olfactory information in the fruitfly Drosophila, axons of ∼50 classes of olfactory receptor neurons (ORNs) form one-to-one connections with dendrites of ∼50 classes of projection neurons (PNs). Here, using genetic screens, we identified two evolutionarily conserved, epidermal growth factor (EGF)-repeat containing transmembrane Teneurin proteins, Ten-m and Ten-a, as synaptic-partner-matching molecules between PN dendrites and ORN axons. Ten-m and Ten-a are highly expressed in select PN-ORN matching pairs. Teneurin loss- and gain-of-function cause specific mismatching of select ORNs and PNs. Finally, Teneurins promote homophilic interactions in vitro, and Ten-m co-expression in non-partner PNs and ORNs promotes their ectopic connections in vivo. We propose that Teneurins instruct matching specificity between synaptic partners through homophilic attraction.
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http://dx.doi.org/10.1038/nature10926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3345284PMC
March 2012

Drosophila Importin-α2 is involved in synapse, axon and muscle development.

PLoS One 2010 Dec 6;5(12):e15223. Epub 2010 Dec 6.

F. M. Kirby Neurobiology Center, Children's Hospital Boston, Boston, Massachusetts, United States of America.

Nuclear import is required for communication between the cytoplasm and the nucleus and to enact lasting changes in gene transcription following stimuli. Binding to an Importin-α molecule in the cytoplasm is often required to mediate nuclear entry of a signaling protein. As multiple isoforms of Importin-α exist, some may be responsible for the entry of distinct cargoes rather than general nuclear import. Indeed, in neuronal systems, Importin-α isoforms can mediate very specific processes such as axonal tiling and communication of an injury signal. To study nuclear import during development, we examined the expression and function of Importin-α2 in Drosophila melanogaster. We found that Importin-α2 was expressed in the nervous system where it was required for normal active zone density at the NMJ and axonal commissure formation in the central nervous system. Other aspects of synaptic morphology at the NMJ and the localization of other synaptic markers appeared normal in importin-α2 mutants. Importin-α2 also functioned in development of the body wall musculature. Mutants in importin-α2 exhibited errors in muscle patterning and organization that could be alleviated by restoring muscle expression of Importin-α2. Thus, Importin-α2 is needed for some processes in the development of both the nervous system and the larval musculature.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0015223PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2997784PMC
December 2010

The nuclear import of Frizzled2-C by Importins-beta11 and alpha2 promotes postsynaptic development.

Nat Neurosci 2010 Aug 4;13(8):935-43. Epub 2010 Jul 4.

The F.M. Kirby Neurobiology Center, Children's Hospital Boston, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.

Synapse-to-nucleus signaling is critical for synaptic development and plasticity. In Drosophila, the ligand Wingless causes the C terminus of its Frizzled2 receptor (Fz2-C) to be cleaved and translocated from the postsynaptic density to nuclei. The mechanism of nuclear import is unknown and the developmental consequences of this translocation are uncertain. We found that Fz2-C localization to muscle nuclei required the nuclear import factors Importin-beta11 and Importin-alpha2 and that this pathway promoted the postsynaptic development of the subsynaptic reticulum (SSR), an elaboration of the postsynaptic plasma membrane. importin-beta11 (imp-beta11) and dfz2 mutants had less SSR, and some boutons lacked the postsynaptic marker Discs Large. These developmental defects in imp-beta11 mutants could be overcome by expression of Fz2-C fused to a nuclear localization sequence that can bypass Importin-beta11. Thus, Wnt-activated growth of the postsynaptic membrane is mediated by the synapse-to-nucleus translocation and active nuclear import of Fz2-C via a selective Importin-beta11/alpha2 pathway.
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http://dx.doi.org/10.1038/nn.2593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2913881PMC
August 2010

Importin-beta11 regulates synaptic phosphorylated mothers against decapentaplegic, and thereby influences synaptic development and function at the Drosophila neuromuscular junction.

J Neurosci 2010 Apr;30(15):5253-68

FM Kirby Center for Neurobiology, Children's Hospital, Boston, Massachusetts 02115, USA.

Importin proteins act both at the nuclear pore to promote substrate entry and in the cytosol during signal trafficking. Here, we describe mutations in the Drosophila gene importin-beta11, which has not previously been analyzed genetically. Mutants of importin-beta11 died as late pupae from neuronal defects, and neuronal importin-beta11 was present not only at nuclear pores but also in the cytosol and at synapses. Neurons lacking importin-beta11 were viable and properly differentiated but exhibited discrete defects. Synaptic transmission was defective in adult photoreceptors and at larval neuromuscular junctions (NMJs). Mutant photoreceptor axons formed grossly normal projections and synaptic terminals in the brain, but synaptic arbors on larval muscles were smaller while still containing appropriate synaptic components. Bone morphogenic protein (BMP) signaling was the apparent cause of the observed NMJ defects. Importin-beta11 interacted genetically with the BMP pathway, and at mutant synaptic boutons, a key component of this pathway, phosphorylated mothers against decapentaplegic (pMAD), was reduced. Neuronal expression of an importin-beta11 transgene rescued this phenotype as well as the other observed neuromuscular phenotypes. Despite the loss of synaptic pMAD, pMAD persisted in motor neuron nuclei, suggesting a specific impairment in the local function of pMAD. Restoring levels of pMAD to mutant terminals via expression of constitutively active type I BMP receptors or by reducing retrograde transport in motor neurons also restored synaptic strength and morphology. Thus, importin-beta11 function interacts with the BMP pathway to regulate a pool of pMAD that must be present at the presynapse for its proper development and function.
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http://dx.doi.org/10.1523/JNEUROSCI.3739-09.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881940PMC
April 2010

Dissection of synaptic excitability phenotypes by using a dominant-negative Shaker K+ channel subunit.

Proc Natl Acad Sci U S A 2005 Mar 22;102(9):3477-82. Epub 2005 Feb 22.

Department of Molecular, Cellular, and Developmental Biology, Yale University, P.O. Box 208103, New Haven, CT 06520-8103, USA.

During nervous system development, synapses undergo morphological change as a function of electrical activity. In Drosophila, enhanced activity results in the expansion of larval neuromuscular junctions. We have examined whether these structural changes involve the pre- or postsynaptic partner by selectively enhancing electrical excitability with a Shaker dominant-negative (SDN) potassium channel subunit. We find that the SDN enhances neurotransmitter release when expressed in motoneurons, postsynaptic potential broadening when expressed in muscles and neurons, and selectively suppresses fast-inactivating, Shaker-mediated IA currents in muscles. SDN expression also phenocopies the canonical behavioral phenotypes of the Sh mutation. At the neuromuscular junction, we find that activity-dependent changes in arbor size occur only when SDN is expressed presynaptically. This finding indicates that elevated postsynaptic membrane excitability is by itself insufficient to enhance presynaptic arbor growth. Such changes must minimally involve increased neuronal excitability.
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http://dx.doi.org/10.1073/pnas.0406164102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC552910PMC
March 2005