Structural Remodeling of Active Zones Is Associated with Synaptic Homeostasis

Perturbations to postsynaptic glutamate receptors (GluRs) trigger retrograde signaling to precisely increase presynaptic neurotransmitter release, maintaining stable levels of synaptic strength, a process referred to as homeostatic regulation. However, the structural change of homeostatic regulation remains poorly defined. At wild-type Drosophila neuromuscular junction synapse, there is one Bruchpilot (Brp) ring detected by superresolution microscopy at active zones (AZs). Perturbations to postsynaptic glutamate receptors (GluRs) trigger retrograde signaling to precisely increase presynaptic neurotransmitter release, maintaining stable levels of synaptic strength, a process referred to as homeostatic regulation. However, the structural change of homeostatic regulation remains poorly defined. At wild-type Drosophila neuromuscular junction synapse, there is one Bruchpilot (Brp) ring detected by superresolution microscopy at active zones (AZs). In the present study, we report multiple Brp rings (i.e., multiple T-bars seen by electron microscopy) at AZs of both male and female larvae when GluRs are reduced. At GluRIIC-deficient neuromuscular junctions, quantal size was reduced but quantal content was increased, indicative of homeostatic presynaptic potentiation. Consistently, multiple Brp rings at AZs were observed in the two classic synaptic homeostasis models (i.e., GluRIIA mutant and pharmacological blockade of GluRIIA activity). Furthermore, postsynaptic overexpression of the cell adhesion protein Neuroligin 1 partially rescued multiple Brp rings phenotype. Our study thus supports that the formation of multiple Brp rings at AZs might be a structural basis for synaptic homeostasis. SIGNIFICANCE STATEMENT Synaptic homeostasis is a conserved fundamental mechanism to maintain efficient neurotransmission of neural networks. Active zones (AZs) are characterized by an electron-dense cytomatrix, which is largely composed of Bruchpilot (Brp) at the Drosophila neuromuscular junction synapses. It is not clear how the structure of AZs changes during homeostatic regulation. To address this question, we examined the structure of AZs by superresolution microscopy and electron microscopy during homeostatic regulation. Our results reveal multiple Brp rings at AZs of glutamate receptor-deficient neuromuscular junction synapses compared with single Brp ring at AZs in wild type (WT). We further show that Neuroligin 1-mediated retrograde signaling regulates multiple Brp ring formation at glutamate receptor-deficient synapses. This study thus reveals a regulatory mechanism for synaptic homeostasis.

[1]  D. Dickman,et al.  Endogenous Tagging Reveals Differential Regulation of Ca2+ Channels at Single Active Zones during Presynaptic Homeostatic Potentiation and Depression , 2019, The Journal of Neuroscience.

[2]  Mathias A. Böhme,et al.  Homeostatic scaling of active zone scaffolds maintains global synaptic strength , 2019, The Journal of cell biology.

[3]  Mathias A. Böhme,et al.  Rapid active zone remodeling consolidates presynaptic potentiation , 2018, Nature Communications.

[4]  Martin Hruska,et al.  Synaptic nanomodules underlie the organization and plasticity of spine synapses , 2018, Nature Neuroscience.

[5]  D. Dickman,et al.  Disparate Postsynaptic Induction Mechanisms Ultimately Converge to Drive the Retrograde Enhancement of Presynaptic Efficacy. , 2017, Cell reports.

[6]  R. Fetter,et al.  Retrograde Semaphorin-Plexin Signaling Drives Homeostatic Synaptic Plasticity , 2017, Nature.

[7]  Y. Goda,et al.  Alternative Splicing of P/Q-Type Ca2+ Channels Shapes Presynaptic Plasticity. , 2017, Cell reports.

[8]  H. Ewers,et al.  Nanoscale Structural Plasticity of the Active Zone Matrix Modulates Presynaptic Function , 2017, Cell reports.

[9]  Christina A. Beis,et al.  Active zone scaffolds differentially accumulate Unc13 isoforms to tune Ca2+ channel–vesicle coupling , 2016, Nature Neuroscience.

[10]  N. Perrimon,et al.  The postsynaptic t-SNARE Syntaxin 4 controls traffic of Neuroligin 1 and Synaptotagmin 4 to regulate retrograde signaling , 2016, eLife.

[11]  M. Pinter,et al.  Reversible Recruitment of a Homeostatic Reserve Pool of Synaptic Vesicles Underlies Rapid Homeostatic Plasticity of Quantal Content , 2016, The Journal of Neuroscience.

[12]  Mathias A. Böhme,et al.  Presynaptic spinophilin tunes neurexin signalling to control active zone architecture and function , 2015, Nature Communications.

[13]  J. Littleton,et al.  Transmission, Development, and Plasticity of Synapses , 2015, Genetics.

[14]  Frank Noé,et al.  Dynamical Organization of Syntaxin-1A at the Presynaptic Active Zone , 2015, PLoS Comput. Biol..

[15]  E. Suzuki,et al.  Molecular Remodeling of the Presynaptic Active Zone of Drosophila Photoreceptors via Activity-Dependent Feedback , 2015, Neuron.

[16]  G. Davis,et al.  Homeostatic control of presynaptic neurotransmitter release. , 2015, Annual review of physiology.

[17]  E. Isacoff,et al.  Evoked and Spontaneous Transmission Favored by Distinct Sets of Synapses , 2014, Current Biology.

[18]  Manuela Schmidt,et al.  The Bruchpilot cytomatrix determines the size of the readily releasable pool of synaptic vesicles , 2013, The Journal of cell biology.

[19]  A. Rodal,et al.  Drosophila cyfip Regulates Synaptic Development and Endocytosis by Suppressing Filamentous Actin Assembly , 2013, PLoS genetics.

[20]  D. Owald,et al.  Cooperation of Syd-1 with Neurexin synchronizes pre- with postsynaptic assembly , 2012, Nature Neuroscience.

[21]  N. Sonenberg,et al.  TOR Is Required for the Retrograde Regulation of Synaptic Homeostasis at the Drosophila Neuromuscular Junction , 2012, Neuron.

[22]  T. Südhof,et al.  Synaptic cell adhesion. , 2012, Cold Spring Harbor perspectives in biology.

[23]  L. Luo,et al.  Transsynaptic Teneurin Signaling in Neuromuscular Synapse Organization and Target Choice , 2012, Nature.

[24]  Stephan J. Sigrist,et al.  RIM-Binding Protein, a Central Part of the Active Zone, Is Essential for Neurotransmitter Release , 2011, Science.

[25]  J. Eilers,et al.  Rapid Active Zone Remodeling during Synaptic Plasticity , 2011, The Journal of Neuroscience.

[26]  G. Davis,et al.  Rab3-GAP Controls the Progression of Synaptic Homeostasis at a Late Stage of Vesicle Release , 2011, Neuron.

[27]  L. Fradkin,et al.  The RhoGAP crossveinless-c Interacts with Dystrophin and Is Required for Synaptic Homeostasis at the Drosophila Neuromuscular Junction , 2011, The Journal of Neuroscience.

[28]  M. Rich,et al.  Activity-dependent regulation of the binomial parameters p and n at the mouse neuromuscular junction in vivo. , 2010, Journal of neurophysiology.

[29]  D. Owald,et al.  Drosophila Neuroligin 1 Promotes Growth and Postsynaptic Differentiation at Glutamatergic Neuromuscular Junctions , 2010, Neuron.

[30]  Y. Goda,et al.  Unraveling Mechanisms of Homeostatic Synaptic Plasticity , 2010, Neuron.

[31]  Manuela Schmidt,et al.  A Syd-1 homologue regulates pre- and postsynaptic maturation in Drosophila , 2010, The Journal of cell biology.

[32]  H. Bellen,et al.  Rab3 GTPase Lands Bruchpilot , 2009, Neuron.

[33]  Robert W. Burgess,et al.  Rab3 Dynamically Controls Protein Composition at Active Zones , 2009, Neuron.

[34]  D. Owald,et al.  Maturation of active zone assembly by Drosophila Bruchpilot , 2009, The Journal of cell biology.

[35]  M. Gustafsson,et al.  Three-dimensional resolution doubling in wide-field fluorescence microscopy by structured illumination. , 2008, Biophysical journal.

[36]  G. Davis,et al.  The BMP Ligand Gbb Gates the Expression of Synaptic Homeostasis Independent of Synaptic Growth Control , 2007, Neuron.

[37]  V. Budnik,et al.  Crucial Role of Drosophila Neurexin in Proper Active Zone Apposition to Postsynaptic Densities, Synaptic Growth, and Synaptic Transmission , 2007, Neuron.

[38]  M. Dalva,et al.  Cell adhesion molecules: signalling functions at the synapse , 2007, Nature Reviews Neuroscience.

[39]  C. A. Frank,et al.  Mechanisms Underlying the Rapid Induction and Sustained Expression of Synaptic Homeostasis , 2006, Neuron.

[40]  M. Nonet,et al.  SYD-2 Liprin-α organizes presynaptic active zone formation through ELKS , 2006, Nature Neuroscience.

[41]  Stephan J. Sigrist,et al.  Bruchpilot Promotes Active Zone Assembly, Ca2+ Channel Clustering, and Vesicle Release , 2006, Science.

[42]  Stephan J. Sigrist,et al.  Bruchpilot, a Protein with Homology to ELKS/CAST, Is Required for Structural Integrity and Function of Synaptic Active Zones in Drosophila , 2006, Neuron.

[43]  Tobias M. Rasse,et al.  Glutamate receptor dynamics organizing synapse formation in vivo , 2005, Nature Neuroscience.

[44]  Tobias M. Rasse,et al.  Four Different Subunits Are Essential for Expressing the Synaptic Glutamate Receptor at Neuromuscular Junctions of Drosophila , 2005, The Journal of Neuroscience.

[45]  D. Featherstone,et al.  An Essential Drosophila Glutamate Receptor Subunit That Functions in Both Central Neuropil and Neuromuscular Junction , 2005, The Journal of Neuroscience.

[46]  H. Bellen,et al.  The architecture of the active zone in the presynaptic nerve terminal. , 2004, Physiology.

[47]  A. Diantonio,et al.  Preferential Localization of Glutamate Receptors Opposite Sites of High Presynaptic Release , 2004, Current Biology.

[48]  I. Lasarzik,et al.  Mouse photoreceptor synaptic ribbons lose and regain material in response to illumination changes , 2004, The European journal of neuroscience.

[49]  A. Diantonio,et al.  Differential Localization of Glutamate Receptor Subunits at the Drosophila Neuromuscular Junction , 2004, The Journal of Neuroscience.

[50]  C. Goodman,et al.  The BMP Homolog Gbb Provides a Retrograde Signal that Regulates Synaptic Growth at the Drosophila Neuromuscular Junction , 2003, Neuron.

[51]  C. Goodman,et al.  Retrograde Control of Synaptic Transmission by Postsynaptic CaMKII at the Drosophila Neuromuscular Junction , 2003, Neuron.

[52]  D. Reiff,et al.  Differential Regulation of Active Zone Density during Long-Term Strengthening of Drosophila Neuromuscular Junctions , 2002, The Journal of Neuroscience.

[53]  C. Goodman,et al.  Glutamate Receptor Expression Regulates Quantal Size and Quantal Content at the Drosophila Neuromuscular Junction , 1999, The Journal of Neuroscience.

[54]  C. Goodman,et al.  Synapse-specific control of synaptic efficacy at the terminals of a single neuron , 1998, Nature.

[55]  C. Goodman,et al.  Genetic analysis of synaptic development and plasticity: homeostatic regulation of synaptic efficacy , 1998, Current Opinion in Neurobiology.

[56]  C. Goodman,et al.  Genetic Analysis of Glutamate Receptors in Drosophila Reveals a Retrograde Signal Regulating Presynaptic Transmitter Release , 1997, Neuron.

[57]  R. Miledi,et al.  On the release of transmitter at normal, myasthenia gravis and myasthenic syndrome affected human end‐plates. , 1980, The Journal of physiology.

[58]  G. Turrigiano.  Homeostatic synaptic plasticity: local and global mechanisms for stabilizing neuronal function. , 2012, Cold Spring Harbor perspectives in biology.