The HSPG Glypican Regulates Experience-Dependent Synaptic and Behavioral Plasticity by Modulating the Non-Canonical BMP Pathway

Abstract

Graphical Abstract Highlights d Octopaminergic signaling regulates postsynaptic Dlp levels during starvation d dlp is required for starvation-induced synaptic growth and locomotor behavior d Dlp regulates GluRIIA-mediated non-canonical BMP signaling d This BMP signaling regulates starvation-induced behavioral and synaptic plasticities SUMMARYUnder food deprivation conditions, Drosophila larvae exhibit increases in locomotor speed and synaptic bouton numbers at neuromuscular junctions (NMJs). Octopamine, the invertebrate counterpart of noradrenaline, plays critical roles in this process; however, the underlying mechanisms remain unclear. We show here that a glypican (Dlp) negatively regulates type I synaptic bouton formation, postsynaptic expression of GluRIIA, and larval locomotor speed. Starvation-induced octopaminergic signaling decreases Dlp expression, leading to increases in synapse formation and locomotion. Dlp is expressed by postsynaptic muscle cells and suppresses the non-canonical BMP pathway, which is composed of the presynaptic BMP receptor Wit and postsynaptic GluRIIA-containing ionotropic glutamate receptor. We find that during starvation, decreases in Dlp increase non-canonical BMP signaling, leading to increases in GluRIIA expression, type I bouton number, and locomotor speed. Our results demonstrate that octopamine controls starvation-induced neural plasticity by regulating Dlp and provides insights into how proteoglycans can influence behavioral and synaptic plasticity.

Dysregulation of BMP, Wnt, and Insulin Signaling in Fragile X Syndrome

“…Later in neurodevelopment, secreted trans -synaptic BMP signaling regulates synaptic structure and function at the Drosophila larval glutamatergic NMJ ( Figure 1 ), including motoneuron terminal growth ( Sulkowski et al, 2016 ; Kamimura et al, 2019 ), neurotransmission strength ( Kamimura et al, 2019 ; Politano et al, 2019 ), and maintained homeostasis ( Chou et al, 2020 ). Three known BMP ligands Decapentaplegic (Dpp), Glass-bottom boat (Gbb), and Screw (Scw) ( Upadhyay et al, 2017 ) are secreted from either presynaptic boutons or postsynaptic muscles to activate BMP type I receptors Thick veins (Tkv) and Saxophone (Sax), and either of two the type II receptors Wishful thinking (Wit) or Punt (Put) ( Kim and O’Connor, 2014 ; Upadhyay et al, 2017 ).…”

“…Nevertheless, the GluRIIA accumulation in the Drosophila FXS model ( Pan and Broadie, 2007 ) is well explained by the postsynaptic FMRP-Stau-Cora regulative pathway, which activates phosphorylation of presynaptic Mothers against Decapentaplegic (Mad) to drive NMJ bouton overgrowth ( Figure 1 ; Song et al, 2022 ). Interestingly, Coracle overexpression and RNAi phenocopy ( Song et al, 2022 ), as in other neurodevelopmental contexts ( Landsverk et al, 2007 ; Tokuda et al, 2014 ; Fulterer et al, 2018 ), and GluRIIA-induced pMad production does not involve BMP ligands ( Friedman et al, 2013 ; Sulkowski et al, 2016 ; Kamimura et al, 2019 ), but does depend on BMP receptors Wit and Sax ( Sulkowski et al, 2016 ; Kamimura et al, 2019 ). GluRIIA is thought to interact with Wit through the transmembrane GluR-clustering protein Neto ( Chou et al, 2020 ), but the mechanism of this FMRP-dependent noncanonical trans -synaptic BMP signaling remains to be fully elucidated.…”

Mechanical Properties of the Extracellular Environment of Human Brain Cells Drive the Effectiveness of Drugs in Fighting Central Nervous System Cancers

“…Most basically, the brain’s ECM biomacromolecule composition consists of: (i) glycosaminoglycans (GAGs)–hyaluronic acid (HA) [ 17 , 22 , 25 ]; (ii) proteoglycans (PGs)–chondroitin sulfate proteoglycans (brevican, versican, neurocan, and phosphacan) [ 22 , 26 , 27 , 28 , 29 , 30 ], and heparan sulfate proteoglycans (syndecan, glypican, agrin, and perlecan) [ 25 , 31 , 32 , 33 ] and (iii) glycoproteins—link proteins, tenascin-R, collagens, fibronectins, laminins, and nidogens [ 3 , 17 , 32 , 34 , 35 , 36 , 37 , 38 ] ( Figure 2 ). The scaffolding for the ECM structure is made up of GAGs, namely HA polymers.…”

“…In the central nervous system (CNS), the two primary types of PGs are chondroitin sulfate proteoglycans and heparin sulfate proteoglycans [ 25 , 31 ]. The most prevalent chondroitin sulfate proteoglycans are lecticans, which are involved in gliogenesis in the developing brain, tissue repair after brain injury or in brain tumors, neuronal adhesion, axonal growth, development of the nervous system, and inhibition of neurite outgrowth [ 25 , 31 , 32 , 33 ].The other type of PGs are involved in binding different proteins, basement membrane association, signaling, structural functions, growth factor signaling and sensitivity, binding proteins during neuronal development, and organization of the basement membrane [ 25 , 31 , 32 , 33 ]. Glycoproteins are engaged in interactions between HA and aggrecan, formation of lectin complexes, antiadhesive and adhesive functions dependent on cell type, expression in tumors, vascular basement membrane, cell development and differentiation, and creation of strong complexes [ 3 , 17 , 22 , 32 , 34 , 35 , 36 , 37 , 38 ].…”

Synapse development and maturation at the drosophila neuromuscular junction

“…Synaptic signaling is also regulated by heparan sulfate proteoglycans (HSPGs) such as Dallylike (Dlp) and Syndecan (Sdc), which impact multiple pathways including Wnt/Wg and BMP [254,255]. Dlp acts as a negative brake on the positive feedback loop between GluRIIA and presynaptic pMad that is itself inhibited by presence of Octopamine, the Drosophila analog of nonadrenaline [256]. Additionally, Dlp and Sdc regulate the RPTP LAR, with effects on presynaptic neuronal morphology and AZ assembly [31,120].…”