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PTX3 regulates synaptic function inducing AMPARs clustering via extracellular matrix and ?1 integrin

ABSTRACT: In the developing central nervous system, the control of synapse number and function are critical to the formation of neural circuits. Astrocytes play a key role in this process by releasing factors, which promote the formation of excitatory synapses. Astrocyte-secreted thrombospondins (TSPs) induce the formation of synapses, which are however post-synaptically silent, suggesting that completion of early synaptogenesis requires a double-step mechanism. Here we show that the humoral innate immune molecule Pentraxin 3 (PTX3) is expressed in the developing rodent brain. PTX3 plays a key role in promoting functionally active CNS synapses, by increasing the surface levels and synaptic clustering of the AMPA glutamate receptors, through a process involving TSG6, the remodeling of the perineuronal network and a ?1 integrin/ERK pathway. Furthermore PTX3 activity is regulated by TSP1, that directly interacts with the N-terminal region of PTX3. These data unveil a fundamental role of PTX3 in promoting the first wave of synaptogenesis and show that the interplay of TSP1 and PTX3 sets the proper balance between synaptic growth and synapse function in the developing brain.

SUBMITTER: Dr. Giuliana Fossati

PROVIDER: S-SCDT-EMBOJ-2018-99529 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:BackgroundCue-induced relapse to drug use is a primary symptom of cocaine addiction. Cue-induced transient excitatory synaptic potentiation (t-SP) induced in the nucleus accumbens mediates cued cocaine seeking in rat models of relapse. Cue-induced t-SP depends on extracellular signaling by matrix metalloproteases (MMPs), but it is unknown how this catalytic activity communicates with nucleus accumbens neurons to induce t-SP and cocaine seeking.MethodsMale Sprague Dawley rats (N = 125) were trained to self-administer cocaine, after which self-administration was extinguished and then reinstated by cocaine-conditioned cues. We used a morpholino antisense strategy to knock down the β1 or β3 integrin subunits or inhibitors to prevent phosphorylation of the integrin signaling kinases focal adhesion kinase (FAK) or integrin-linked kinase. We quantified protein changes with immunoblotting and t-SP by measuring dendritic spine morphology and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/N-methyl-D-aspartate glutamate currents. Integrin signaling was stimulated by microinjecting an MMP activator or integrin peptide ligand into the accumbens.ResultsKnockdown of β3 integrin or FAK inhibitor, but not β1 integrin or integrin-linked kinase inhibitor, prevented cue-induced cocaine seeking but not sucrose seeking. β3 integrin knockdown prevented t-SP as measured by preventing the cue-induced increases in both alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/N-methyl-D-aspartate glutamate ratio and spine head diameter. Activating MMP gelatinases with tissue plasminogen activator potentiated cue-induced reinstatement, which was prevented by β3 integrin knockdown and FAK inhibition. Stimulating integrin receptors with the RGD ligand liberated by MMP gelatinase activity also potentiated cued cocaine seeking.ConclusionsActivation of MMP gelatinase in the extracellular space is necessary for and potentiates cued cocaine seeking. This extracellular catalysis stimulates β3 integrins and activates FAK to induce t-SP and promote cue-induced cocaine seeking.

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PTX3 regulates synaptic function inducing AMPARs clustering via extracellular matrix and ?1 integrin

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