The calcium channel subunit α2δ-3 organizes synapses via an activity-dependent and autocrine BMP signaling pathway

Abstract

Synapses are highly specialized for neurotransmitter signaling, yet activity-dependent growth factor release also plays critical roles at synapses. While efficient neurotransmitter signaling relies on precise apposition of release sites and neurotransmitter receptors, molecular mechanisms enabling high-fidelity growth factor signaling within the synaptic microenvironment remain obscure. Here we show that the auxiliary calcium channel subunit α 2 δ-3 promotes the function of an activity-dependent autocrine Bone Morphogenetic Protein (BMP) signaling pathway at the Drosophila neuromuscular junction (NMJ). α 2 δ proteins have conserved synaptogenic activity, although how they execute this function has remained elusive. We find that α 2 δ-3 provides an extracellular scaffold for an autocrine BMP signal, suggesting a mechanistic framework for understanding α 2 δ's conserved role in synapse organization. We further establish a transcriptional requirement for activity-dependent, autocrine BMP signaling in determining synapse density, structure, and function. We propose that activity-dependent, autocrine signals provide neurons with continuous feedback on their activity state for modulating both synapse structure and function.

Synapse development and maturation at the drosophila neuromuscular junction

“…Autocrine signaling occurs when an activity dependent stimulus promotes release and reabsorption of Gbb by the motorneuron, triggering a locally sustained BMP response. Recently, a calcium channel subunit (α 2 δ-3) was found to physically interact with neuronally-derived Gbb and was required to limit the range at which Gbb could work to strengthen the synapse [248].…”

“…How then does the motor neuron distinguish between these two signals to regulate two separable functions (bouton growth and synaptic (AZ) density)? Temporal requirements for each type signal partially explain the separability as the muscle-derived growth signal is primarily needed early phases (L1), while the sustained neuronally derived signal is required at later stages to refine and strengthen the synapse [248]. Additionally, factors that interact with Gbb can also separate functions.…”

Neuronal α2δ proteins and brain disorders

“…A recent study might offer a mechanistic explanation how the extracellular α 2 peptide of α 2 δ-3 regulates the development of embryonic Drosophila NMJs. Hoover et al [ 47 ] uncovered that presynaptic α 2 δ-3 promotes the function of an activity-dependent autocrine bone morphogenetic protein (BMP) signaling pathway via modulating membrane retention of glass bottom boat (Gbb). Presynaptic Gbb, in turn, serves as a retrograde cue regulating active zone architecture, synaptic vesicle distribution, neurotransmitter release, and bouton morphogenesis.…”

Glia-neuron signaling mediated by two different BMP ligands impacts synaptic growth

“…In Drosophila, a number of studies to date have characterized roles for BMP signaling in the development of the nervous system, as well as in ensuring its proper function. glass bottom boat ( gbb ), the gene encoding the Drosophila BMP5/6/7/8 orthologous ligand, Gbb (Wharton et al 1991), has a demonstrated role in both growth and function of the larval neuromuscular junction (NMJ), as well as synaptic plasticity (Berke et al 2019; Berke et al 2013; Goold and Davis 2007; Hoover et al 2019; James and Broihier 2011; James et al 2014; McCabe et al 2003; Sulkowski et al 2014). Active BMP signaling is first evident in the embryonic nervous system at stage 15 with the nuclear localization in a subset of neurons of pMad, the phosphorylated Drosophila R-Smad1/5/8, an indication that these neurons have received a BMP signal (Marques et al 2002).…”

“…A proposed role for a neuronal pool of Gbb in neurotransmitter release emerged most recently from experiments in which expressing gbb in neurons results in trafficking of Gbb in dense core vesicles with neuronal factor Crimpy (Cmpy) (James et al 2014) and the neuronal expression of gbb -RNAi in a gbb null heterozygote phenocopies the synaptic defects. associated with calcium channel α 2 δ-3 mutants (Hoover et al 2019). In its earlier requirement for synapse growth and later as a facilitator of neurotransmission, the activation of BMP signaling by Gbb involves pMad-mediated signaling (Berke et al 2013; Hoover et al 2019).…”