Target‐dependent retrograde signaling mediates synaptic plasticity at theDrosophilaneuromuscular junction

Abstract

Neurons that innervate multiple targets often establish synapses with target‐specific strengths, and local forms of synaptic plasticity. We have examined the molecular‐genetic mechanisms that allow a single Drosophila motoneuron, the ventral Common Exciter (vCE), to establish connections with target‐specific properties at its various synaptic partners. By driving transgenes in a subset of vCE’s targets, we found that individual target cells are able to independently control the properties of vCE's innervating branch and synapses. This is achieved by means of a trans‐synaptic growth factor secreted by the target cell. At the larval neuromuscular junction, postsynaptic glutamate receptor activity stimulates the release of the BMP4/5/6 homolog Glass bottom boat (Gbb). As larvae mature and motoneuron terminals grow, Gbb activates the R‐Smad transcriptional regulator phosphorylated Mad (pMad) to facilitate presynaptic development. We found that manipulations affecting glutamate receptors or Gbb within subsets of target muscles led to local effects either specific to the manipulated muscle or by a limited gradient within the presynaptic branches. While presynaptic development depends on pMad transcriptional activity within the motoneuron nucleus, we find that the Gbb growth factor may also act locally within presynaptic terminals. Local Gbb signaling and presynaptic pMad accumulation within boutons may therefore participate in a “synaptic tagging” mechanism, to influence synaptic growth and plasticity in Drosophila.

ActRIIB:ALK4-Fc alleviates muscle dysfunction and comorbidities in murine models of neuromuscular disorders

“…ActRIIB:ALK4-Fc might improve NMJ structure and function in part by modulating the balance of muscle-derived retrograde signaling mediated by TGF-β superfamily ligands. Studies in Drosophila indicate that retrograde trans-synaptic signaling by BMPs released from target muscle fibers or neurons supports NMJ growth, neurotransmission, and synaptic plasticity (72)(73)(74). Additionally, myoglianin (MYO), the Drosophila homolog of GDF8 and GDF11, was found to negatively regulate synaptic function and neuronal morphology, which affected both NMJ strength and composition (75).…”

Structure–function relation of the developing calyx of Held synapse in vivo

“…In the fruit fly postsynaptic activity stimulates the release of bone morphogenetic protein (BMP) homologue, which promotes active zone development and NMJ growth (Berke et al . 2013, 2019). Mice with conditionally deleted BMP receptor 1 and 2 show deficits in transmitter release and smaller calyces (Xiao et al .…”

“…After hearing onset the NMDA receptors are down-regulated (Taschenberger & von Gersdorff, 2000;Futai et al 2001;Joshi & Wang, 2002;Steinert et al 2010) and calcium buffering proteins up-regulated in the MNTB (Lohmann & Friauf, 1996;Felmy & Schneggenburger, 2004;Kolson et al 2016), possibly limiting the impact of postsynaptic calcium signals to instruct activity-dependent synapse development to a brief period during development. In the fruit fly postsynaptic activity stimulates the release of bone morphogenetic protein (BMP) homologue, which promotes active zone development and NMJ growth (Berke et al 2013(Berke et al , 2019. Mice with conditionally deleted BMP receptor 1 and 2 show deficits in transmitter release and smaller calyces (Xiao et al 2013) in addition to a persistence of axonal branches with calyces and increased multi-calyceal innervation (Kronander et al 2019).…”

BMP/TGF‐β signaling as a modulator of neurodegeneration in ALS

“…140,141 The functional difference between "nuclear pMad" and "synaptic pMad" has not been fully elucidated; however, several studies suggest that roles for BMP signaling in synaptic growth and synaptic function are separable. 131,133,141,142 Interestingly, in the dSod1 G85R knock-in model, "synaptic pMad" is elevated indicating that BMP signaling is upregulated at the NMJ. However, no change in pMad levels is apparent in motor neuron nuclei.…”