Synaptic Strengthening Mediated by Bone Morphogenetic Protein-Dependent Retrograde Signaling in theDrosophilaCNS

Abstract

Retrograde signaling is an essential component of synaptic development and physiology. Previous studies show that bone morphogenetic protein (BMP)-dependent retrograde signaling is required for the proper development of the neuromuscular junction (NMJ) in Drosophila. These studies, moreover, raised the significant possibility that the development of central motor circuitry might similarly be reliant on such signaling. To test this hypothesis, retrograde signaling between postsynaptic motoneurons and their presynaptic interneurons is examined. Postsynaptic expression of an adenylate cyclase encoded by rutabaga (rut), is sufficient to strengthen synaptic transmission at these identified central synapses. Results are presented to show that the underlying mechanism is dependent on BMP retrograde signaling. Thus, presynaptic expression of an activated TGF-␤ receptor, thickvien (tkv), or postsynaptic expression of a TGF-␤ ligand, glass-bottom boat ( gbb), is sufficient to phenocopy strengthening of synaptic transmission. In the absence of gbb, endogenous synaptic transmission is significantly weakened and, moreover, postsynaptic overexpression of rut is unable to potentiate synaptic function. Potentiation of presynaptic neurotransmitter release, mediated by increased postsynaptic expression of gbb, is dependent on normal cholinergic activity, indicative that either the secretion of this retrograde signal, or its transduction, is activity dependent. Thus, in addition to the development of the NMJ and expression of myoactive FMRFamide-like peptides in specific central neurons, the results of the present study indicate that this retrograde signaling cascade also integrates the development and function of central motor circuitry that controls movement in Drosophila larvae.

Identification of downstream targets of the Bone Morphogenetic Protein pathway in the Drosophila nervous system

“…While the overwhelming evidence indicates that all Wit responses in motoneurons are mediated through Smads, it is also possible that some non-canonical pathways contribute to BMP neuronal signaling (Baines, 2004;Eaton and Davis, 2005;Sun et al, 2007). To the extent that these Smadindependent pathways operate through transcriptional regulation (Lee et al, 2007), their targets would also have been identified in this screen.…”

“…BMP signaling is also required as a permissive signal to allow fast homeostatic presynaptic plasticity in response to decreased postsynaptic responsiveness at the neuromuscular junction (NMJ) synapse (Goold and Davis, 2007). In addition to its functions at the NMJ, BMP signaling is also required for proper specification of some FMRFamidergic neurons (Allan et al, 2003;Marqués et al, 2003), synaptic transmission between interneurons and motoneurons (Baines, 2004), and eclosion behavior, likely through the regulation of genes of the neuroendocrine axis. This retrograde signaling activity of BMPs has also been described in the mammalian nervous system.…”

“…The mechanisms that underlie synaptic plasticity regulation by BMPs appear to be diverse in different biological contexts. While synaptic growth at the Drosophila larval NMJ and neurosecretory cell specification require the activity of the transcriptional regulators of the Smad family Mad and Medea (Marqués et al, 2002(Marqués et al, , 2003Allan et al, 2003;Rawson et al, 2003;McCabe et al, 2004), synaptic plasticity at the interneuron-motoneuron synapse appears to be independent of Mad (Baines, 2004). In the mouse hippocampus, the BMP-induced enhancement of synaptic transmission appears to be transcription-independent, based on the fast time course of the response (Sun et al, 2007).…”

Dystrophin Is Required for Appropriate Retrograde Control of Neurotransmitter Release at theDrosophilaNeuromuscular Junction

“…The BMP pathway plays an important role in retrograde signaling at the larval NMJ (for review, see Keshishian and Kim, 2004) and in the Drosophila CNS (Baines, 2004). To evaluate the role of BMP signaling in the increase in neurotransmitter release induced by the absence of dystrophin, we performed electrophysiological recordings at NMJs lacking both dystrophin and wit (Fig.…”

Canonical TGF-β Signaling Is Required for the Balance of Excitatory/Inhibitory Transmission within the Hippocampus and Prepulse Inhibition of Acoustic Startle

“…TGF-␤ signaling also regulates synaptic transmission and plasticity in multiple circuits in different organisms including glutamergic transmission at the Drosophila neural muscular junction (McCabe et al, 2004), cholinergic transmission between motoneurons and interneurons in the CNS of Drosophila (Baines, 2004), glutamergic transmission between sensory and motor neurons in Aplysia ganglia (Zhang et al, 1997), and modulation of hippocampal network in mammals (Fukushima et al, 2007;Sun et al, 2007;Zheng et al, 2009).…”