Editors' ChoiceSynaptic Plasticity

Lysosomes get into the action

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Sci. Signal.  24 Jan 2017:
Vol. 10, Issue 463, eaam8020
DOI: 10.1126/scisignal.aam8020

Activity-dependent lysosomal fusion with the plasma membrane stimulates dendrite remodeling.

Neurons exhibit persistent morphological changes in dendrite size and shape in response to synaptic activity. These structural changes require remodeling of the extracellular matrix, a process prevented by the protein TIMP-1, an inhibitor of matrix metalloproteases (MMPs). Padamsey et al. found that inhibition of lysosome function (with the chemical GPN), lysosomal Ca2+ storage (with the chemicals monensin or bafilomycin), lysosome-mediated Ca2+ release (with the NAADP antagonist NED-19), or lysosomal fusion with the plasma membrane (with the cytoplasmic domain of recombinant synaptotagmin 7) reduced Ca2+ signals evoked by back-propagating action potentials and impaired activity–induced persistent enlargement of dendritic spines in hippocampal slice preparations. Electrophysiological experiments indicated that Ca2+ influx through voltage-gated calcium ion channels (VGCCs) was required for the lysosomal-mediated Ca2+ signal that occurred during back-propagating action potentials. Activity-dependent fusion of lysosomes was detected by fusing SEP [a pH-sensitive form of green fluorescent protein (GFP)] to the luminal portion of the lysosomal membrane protein LAMP2. Monitoring LAMP2-SEP fluorescence in dissociated neuronal cultures revealed that the increase in lysosomal fusion triggered by depolarization to activate VGCCs required NAADP-mediated release of Ca2+ from the lysosomes even in the presence of increased extracellular Ca2+. In hippocampal slices, the extracellular activity of cathepsin B, a lysosomal protease active at both neutral and acidic pH values, increased in response to depolarization, and depolarization-induced increase in MMP activity depended on NAADP-mediated lysosomal fusion and cathepsin B activity. Blocking lysosomal fusion with the plasma membrane with the synaptotagmin 7 domain or the NAADP inhibitor NED-19 prevented stable expansion of activated dendritic spines in hippocampal slices. Addition of cathepsin B when lysosomal fusion was blocked restored spine expansion. Pharmacological inhibition of extracellular cathepsin B activity also impaired spine expansion, which was rescued by the addition of MMP9. Thus, lysosomes participate in synaptic plasticity by undergoing regulated fusion with the plasma membrane to release enzymes that enable dendritic remodeling.

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