Neuronal activity drives FMRP- and HSPG-dependent matrix metalloproteinase function required for rapid synaptogenesis

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Science Signaling  07 Nov 2017:
Vol. 10, Issue 504, eaan3181
DOI: 10.1126/scisignal.aan3181

Restraining MMPs or surface glypicans may treat FXS

The breakdown of the extracellular matrix, such as by matrix metalloproteinases (MMPs), helps cells to make protrusions and migrate. In neurons, this activity facilitates the growth and development of boutons that enable synaptogenesis, neuronal adaptability, and memory formation. MMP function is abnormally increased in patients with the intellectual disorder fragile X syndrome (FXS), whose neurons exhibit synaptic dysfunction and increased numbers of immature dendritic spines. In the FXS fly model, the abundance of the heparan sulfate proteoglycan receptor Dlp is also increased. Using flies, Dear et al. found that Dlp directly interacted with and recruited MMP1 to the neuronal cell surface, facilitating its secretion and activity underlying FXS-associated neurological phenotypes. Homologs of both exist in humans, suggesting a potential avenue for therapeutic development.


Matrix metalloproteinase (MMP) functions modulate synapse formation and activity-dependent plasticity. Aberrant MMP activity is implicated in fragile X syndrome (FXS), a disease caused by the loss of the RNA-binding protein FMRP and characterized by neurological dysfunction and intellectual disability. Gene expression studies in Drosophila suggest that Mmps cooperate with the heparan sulfate proteoglycan (HSPG) glypican co-receptor Dally-like protein (Dlp) to restrict trans-synaptic Wnt signaling and that synaptogenic defects in the fly model of FXS are alleviated by either inhibition of Mmp or genetic reduction of Dlp. We used the Drosophila neuromuscular junction (NMJ) glutamatergic synapse to test activity-dependent Dlp and Mmp intersections in the context of FXS. We found that rapid, activity-dependent synaptic bouton formation depended on secreted Mmp1. Acute neuronal stimulation reduced the abundance of Mmp2 but increased that of both Mmp1 and Dlp, as well as enhanced the colocalization of Dlp and Mmp1 at the synapse. Dlp function promoted Mmp1 abundance, localization, and proteolytic activity around synapses. Dlp glycosaminoglycan (GAG) chains mediated this functional interaction with Mmp1. In the FXS fly model, activity-dependent increases in Mmp1 abundance and activity were lost but were restored by reducing the amount of synaptic Dlp. The data suggest that neuronal activity-induced, HSPG-dependent Mmp regulation drives activity-dependent synaptogenesis and that this is impaired in FXS. Thus, exploring this mechanism further may reveal therapeutic targets that have the potential to restore synaptogenesis in FXS patients.

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