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The Journal of Neuroscience, May 7, 2008, 28(19):5105-5114; doi:10.1523/JNEUROSCI.4950-07.2008

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Cellular/Molecular
The Dystrophin Dp186 Isoform Regulates Neurotransmitter Release at a Central Synapse in Drosophila

Lee G. Fradkin,^1 * Richard A. Baines,^2 * Mariska C. van der Plas,¹ and Jasprina N. Noordermeer¹

¹Laboratory of Developmental Neurobiology, Department of Molecular and Cell Biology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands, and ²Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom

Correspondence should be addressed to either Jasprina N. Noordermeer or Lee G. Fradkin, Laboratory of Developmental Neurobiology, Department of Molecular and Cell Biology, Leiden University Medical Center, Einthovenweg 20, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Email: J.N.Noordermeer{at}lumc.nl or Email: L.G.Fradkin{at}lumc.nl

The Dystrophin protein is encoded by a gene that, when mutated in humans, can cause Duchenne muscular dystrophy, a disease characterized by progressive muscle wasting. A number of Duchenne patients also exhibit poorly understood mental retardation, likely associated with loss of a brain-specific isoform. Furthermore, although Dystrophin isoforms and the related Utrophin protein have long been known to localize at synapses, their functions remain essentially unknown. In Drosophila, we find that the CNS-specific Dp186 isoform localizes to the embryonic and larval neuropiles, regions rich in synaptic contacts. In the absence of Dp186, evoked but not spontaneous presynaptic release is significantly enhanced. Increased presynaptic release can be fully rescued to wild-type levels by expression of a Dp186 transgene in the postsynaptic motoneuron, indicating that Dp186 likely regulates a retrograde signaling pathway. Potentiation of synaptic currents in the mutant also occurs when cholinergic transmission is inhibited or in the absence of Glass Bottom Boat (Gbb) or Wishful Thinking (Wit), a TGF-β ligand and receptor, respectively, both previously implicated in synaptic retrograde signaling. These results are consistent with the possibility that Dp186 modulates other non-Gbb/Wit-dependent retrograde signaling pathways required to maintain normal synaptic physiology.

Key words: dystrophin; Drosophila; retrograde signaling; CNS; gbb; interneuronal synapse

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Received Oct. 6, 2006; revised Feb. 2, 2008; accepted March 31, 2008.

Correspondence should be addressed to either Jasprina N. Noordermeer or Lee G. Fradkin, Laboratory of Developmental Neurobiology, Department of Molecular and Cell Biology, Leiden University Medical Center, Einthovenweg 20, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Email: J.N.Noordermeer{at}lumc.nl or Email: L.G.Fradkin{at}lumc.nl

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