, 2002, Hartmann et al., 2001, Kolarow et al., 2007 and Kuczewski et al., 2008). Alternatively, BDNF could be directly mobilized to the PM in Golgi carriers or through a Golgi-to-endosome pathway, but more experiments are required to unravel the subcellular trafficking itinerary of dendritically released neurotrophins. Retrograde neurotrophic signaling has also been observed at the Drosophila neuromuscular junction (NMJ). Muscle-derived factors are known to coordinate NMJ growth during development. For example, the BMP homolog glass selleck chemicals llc bottom boat (Gbb) is secreted from muscle and binds to the presynaptic BMP receptor wishful thinking (Wit), which is known to initiate a BMP signaling cascade culminating in

nuclear accumulation of P-Mad ( McCabe et al., selleck inhibitor 2004 and McCabe et al., 2003). Mutant animals lacking Gbb have smaller NMJs and disorganized presynaptic terminals and lack nuclear accumulation of P-MAD, phenotypes that overlap with Wit null animals. Evidence that Gbb acts in a retrograde manner comes from rescuing Gbb null animals with a muscle-specific promoter, which results in restored synapse size, bouton number, and levels of nuclear P-MAD in motoneurons ( McCabe et al., 2003). Retrograde signaling has also been found to have robust effects on presynaptic vesicle release probability at the Drosophila NMJ. Blocking postsynaptic glutamate

receptors by genetic deletion of GluRIIA initiates a compensatory increase in vesicle release probability that precisely offsets decreased postsynaptic responsiveness to glutamate ( Petersen et al., 1997). Surprisingly, this retrograde signaling pathway could also be activated within minutes by acute introduction of the pharmacological glutamate receptor inhibitor philanthotoxin to NMJ preparations ( Frank et al., 2006). This experiment demonstrates that pre- and postsynaptic compartments are in constant communication Rolziracetam with one another and that changes

in muscle responsiveness can be quickly compensated through modulating the probability of presynaptic vesicle release. It is not yet known whether this form of homeostatic plasticity requires vesicular fusion in muscle or whether a membrane permeable signal is generated that can freely diffuse from muscle to axon terminals. A different form of retrograde plasticity at the Drosophila NMJ involves postsynaptic vesicular fusion. Following strong stimulation, the frequency of presynaptic spontaneous vesicle release increases for minutes ( Yoshihara et al., 2005). Ca2+ is required for this effect and it is blocked at restrictive temperatures by postsynaptic expression of the temperature-sensitive dynamin mutant shibirets1, which is required for compensatory endocytosis following vesicle fusion. These data suggest that ongoing endocytosis in muscle is required for this presynaptic effect, perhaps by generation of postsynaptic endocytic vesicles.