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.

Hebbian plasticity is thought to require glutamate signalling. We show this is not the case for hippocampal presynaptic long-term potentiation (LTPpre), which is expressed as an increase in transmitter release probability (Pr). We find that LTPpre can be induced by pairing pre- and postsynaptic spiking in the absence of glutamate signalling. LTPpre induction involves a non-canonical mechanism of retrograde nitric oxide signalling, which is triggered by Ca2+ influx from L-type voltage-gated Ca2+ channels, not postsynaptic NMDA receptors (NMDARs), and does not require glutamate release. When glutamate release occurs, it decreases Pr by activating presynaptic NMDARs, and promotes presynaptic long-term depression. Net changes in Pr, therefore, depend on two opposing factors: (1) Hebbian activity, which increases Pr, and (2) glutamate release, which decreases Pr. Accordingly, release failures during Hebbian activity promote LTPpre induction. Our findings reveal a novel framework of presynaptic plasticity that radically differs from traditional models of postsynaptic plasticity.

Background:Equinatoxin II is a model ␣-pore-forming toxin that kills cells by porating the host plasma membrane. Results: On the membrane, equinatoxin II does not adopt a unique oligomeric state, but assembles into multiple coexisting species related to toxicity. Conclusion: Toxicity of Equinatoxin II depends on its assembly mechanism. Significance: A new molecular mechanism is proposed for ␣-pore-forming toxins action.

Highlights d Potentiation of spatially clustered synapses induces heterosynaptic plasticity d Heterosynaptic plasticity is expressed at both pre-and postsynaptic terminals d The polarity of neighboring pre-and postsynaptic plasticity is distance dependent d Multiple signaling pathways differentially contribute to heterosynaptic plasticity

Implanted gradient index lenses have extended the reach of standard multiphoton microscopy from the upper layers of the mouse cortex to the lower cortical layers and even subcortical regions. These lenses have the clarity to visualize dynamic activities, such as calcium transients, with subcellular and millisecond resolution and the stability to facilitate repeated imaging over weeks and months. In addition, behavioral tests can be used to correlate performance with observed changes in network function and structure that occur over time. Yet, this raises the questions, does an implanted microlens have an effect on behavioral tests, and if so, what is the extent of the effect? To answer these questions, we compared the performance of three groups of mice in three common behavioral tests. A gradient index lens was implanted in the prefrontal cortex of experimental mice. We compared their performance with mice that had either a cranial window or a sham surgery. Three presurgical and five postsurgical sets of behavioral tests were performed over seven weeks. Behavioral tests included rotarod, foot fault, and Morris water maze. No significant differences were found between the three groups, suggesting that microlens implantation did not affect performance. The results for the current study clear the way for combining behavioral studies with gradient index lens imaging in the prefrontal cortex, and potentially other regions of the mouse brain, to study structural, functional, and behavioral relationships in the brain.