Activity-Dependent Exocytosis of Lysosomes Regulates the Structural Plasticity of Dendritic Spines

Abstract

SummaryLysosomes have traditionally been viewed as degradative organelles, although a growing body of evidence suggests that they can function as Ca2+ stores. Here we examined the function of these stores in hippocampal pyramidal neurons. We found that back-propagating action potentials (bpAPs) could elicit Ca2+ release from lysosomes in the dendrites. This Ca2+ release triggered the fusion of lysosomes with the plasma membrane, resulting in the release of Cathepsin B. Cathepsin B increased the activity of matrix metalloproteinase 9 (MMP-9), an enzyme involved in extracellular matrix (ECM) remodelling and synaptic plasticity. Inhibition of either lysosomal Ca2+ signaling or Cathepsin B release prevented the maintenance of dendritic spine growth induced by Hebbian activity. This impairment could be rescued by exogenous application of active MMP-9. Our findings suggest that activity-dependent exocytosis of Cathepsin B from lysosomes regulates the long-term structural plasticity of dendritic spines by triggering MMP-9 activation and ECM remodelling.

BORC/kinesin-1 ensemble drives polarized transport of lysosomes into the axon

“…3G and Movie S4). This fluorescence could result from fusion of lysosomes with the plasma membrane, as previously reported in other cells (29,(41)(42)(43).…”

F‐actin patches associated with glutamatergic synapses control positioning of dendritic lysosomes

“…They found that about half of the LAMP1‐labeled structures contained functional lysosomal proteases cathepsins B and D, markers for mature lysosomes (Cheng et al , ). It has also been shown that neuronal activity induces lysosomal exocytosis and release of cathepsins (Padamsey et al , ). The spatially and temporally controlled cathepsin B release from mature lysosomes may be a critical step required for input‐specific synaptic potentiation.…”

F-actin patches associated with glutamatergic synapses control positioning of dendritic lysosomes

“…They found that about half of the LAMP1labelled structures contained functional lysosomal proteases cathepsin B and D, markers for mature lysosomes (Cheng et al, 2018). It has also been shown that neuronal activity induces lysosomal exocytosis and release of cathepsins (Padamsey et al, 2017). The spatially and temporally controlled cathepsin B release from mature lysosomes may be a critical step required for input-specific synaptic potentiation.…”

“…To address the question if dendritic actin patches influence organelle trafficking, we chose to look at lysosomes as a representative vesicular organelle, because they show very active, processive trafficking along dendrites, and recently more and more studies are emerging that highlight their significance in neuronal function (Cheng et al, 2018;Goo et al, 2017;Padamsey et al, 2017). First, we used 3-color STED to visualize the spatial relationship between F-actin, MTs and lysosomes, using antibodies against the lysosomal marker protein LAMP1.…”

“…In addition, neuronal activity can trigger the Ca 2+ -dependent fusion of lysosomes with the dendritic plasma membrane, resulting in the release of lysosomal proteases, including cathepsin B. This leads to the activation of matrix metalloproteinase 9, which is instrumental for the remodelling of the extracellular matrix that in turn allows spine growth and long-term potentiation (Padamsey et al, 2017).…”