Inouye, M. O. | bioRxiv Science

bioRxiv2026

Synaptotagmin 7 differentially regulates synaptic vesicle trafficking at tonic and phasic synapses

Synaptic vesicle (SV) release probability can differ across neuronal subtypes, but the molecular mechanisms establishing such differences remain incompletely understood. In the current study we demonstrate that Synaptotagmin 7 (SYT7), a calcium-sensor regulating SV trafficking, is enriched at Drosophila tonic Ib synapses compared with phasic Is synapses. Loss of SYT7 preferentially enhanced evoked release at Ib terminals, whereas overexpression strongly suppressed fusion at both neuronal subtypes. High-frequency stimulation partially overcomes this inhibition, producing robust facilitation. Ultrastructural analysis revealed that SYT7 overexpression preserved morphologically docked SVs while promoting accumulation of enlarged presynaptic cisternae and redistribution of SV-associated proteins. Conversely, SYT7 loss reduced activity-induced presynaptic cisternae, suggesting an important role in regulating the bulk endocytosis pathway. Together, these findings identify differential SYT7 abundance as a contributor to tonic and phasic synaptic diversity and reveal a role for SYT7 in coordinating SV release and presynaptic membrane cycling.

neuroscience↗

bioRxiv2022

miR-329 and miR-495-mediated Prr7 downregulation isrequired for homeostatic synaptic depression in rathippocampal neurons

Homeostatic synaptic depression (HSD) in excitatory neurons is a cell autonomous mechanism which protects excitatory neurons from over-excitation as a consequence of chronic increases in network activity. In this process, excitatory synapses are weakened and eventually eliminated, as evidenced by a reduction in synaptic AMPA receptor expression and dendritic spine loss. Originally considered a global, cell-wide mechanism, local forms of regulation, such as the local control of mRNA translation in dendrites, are being increasingly recognized in HSD. Yet, identification of excitatory proteins whose local regulation is required for HSD is still limited. Here, we show that Proline-rich protein 7/Transmembrane Adapter Protein 3 (Prr7) downregulation in dendrites of rat hippocampal neurons is necessary for HSD induced by chronic increase in network activity resulting from a blockade of inhibitory synaptic transmission by picrotoxin (PTX). We further identify two activity-regulated miRNAs, miR-329-3p and miR-495-3p, which inhibit Prr7 mRNA translation and are required for HSD. Moreover, we found that Prr7 knockdown reduces expression of the synaptic scaffolding protein SPAR, which is rescued by pharmacological inhibition of CDK5, indicating a role of Prr7 protein in the maintenance of excitatory synapses via protection of SPAR from degradation. Together, our findings highlight a novel HSD mechanism in which chronic activity leads to miR-329 and miR-495-mediated local Prr7 reduction upstream of the CDK5-SPAR pathway.

neuroscience↗