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  1. Jędrzejewska-Szmek, Joanna (Ed.)
    Chemical synapses exhibit a diverse array of internal mechanisms that affect the dynamics of transmission efficacy. Many of these processes, such as release of neurotransmitter and vesicle recycling, depend strongly on activity-dependent influx and accumulation of Ca 2+ . To model how each of these processes may affect the processing of information in neural circuits, and how their dysfunction may lead to disease states, requires a computationally efficient modelling framework, capable of generating accurate phenomenology without incurring a heavy computational cost per synapse. Constructing a phenomenologically realistic model requires the precise characterization of the timing and probability of neurotransmitter release.more »Difficulties arise in that functional forms of instantaneous release rate can be difficult to extract from noisy data without running many thousands of trials, and in biophysical synapses, facilitation of per-vesicle release probability is confounded by depletion. To overcome this, we obtained traces of free Ca 2+ concentration in response to various action potential stimulus trains from a molecular MCell model of a hippocampal Schaffer collateral axon. Ca 2+ sensors were placed at varying distance from a voltage-dependent calcium channel (VDCC) cluster, and Ca 2+ was buffered by calbindin. Then, using the calcium traces to drive deterministic state vector models of synaptotagmin 1 and 7 (Syt-1/7), which respectively mediate synchronous and asynchronous release in excitatory hippocampal synapses, we obtained high-resolution profiles of instantaneous release rate, to which we applied functional fits. Synchronous vesicle release occurred predominantly within half a micron of the source of spike-evoked Ca 2+ influx, while asynchronous release occurred more consistently at all distances. Both fast and slow mechanisms exhibited multi-exponential release rate curves, whose magnitudes decayed exponentially with distance from the Ca 2+ source. Profile parameters facilitate on different time scales according to a single, general facilitation function. These functional descriptions lay the groundwork for efficient mesoscale modelling of vesicular release dynamics.« less
    Free, publicly-accessible full text available May 9, 2023
  2. Free, publicly-accessible full text available April 1, 2023
  3. Abstract Long-term depression (LTD) of synaptic strength can take multiple forms and contribute to circuit remodeling, memory encoding or erasure. The generic term LTD encompasses various induction pathways, including activation of NMDA, mGlu or P2X receptors. However, the associated specific molecular mechanisms and effects on synaptic physiology are still unclear. We here compare how NMDAR- or P2XR-dependent LTD affect synaptic nanoscale organization and function in rodents. While both LTDs are associated with a loss and reorganization of synaptic AMPARs, only NMDAR-dependent LTD induction triggers a profound reorganization of PSD-95. This modification, which requires the autophagy machinery to remove the T19-phosphorylatedmore »form of PSD-95 from synapses, leads to an increase in AMPAR surface mobility. We demonstrate that these post-synaptic changes that occur specifically during NMDAR-dependent LTD result in an increased short-term plasticity improving neuronal responsiveness of depressed synapses. Our results establish that P2XR- and NMDAR-mediated LTD are associated to functionally distinct forms of LTD.« less
    Free, publicly-accessible full text available December 1, 2022
  4. Abstract Short-term plasticity preserves a brief history of synaptic activity that is communicated to the postsynaptic neuron. This is primarily regulated by a calcium signal initiated by voltage dependent calcium channels in the presynaptic terminal. Imaging studies of CA3-CA1 synapses reveal the presence of another source of calcium, the endoplasmic reticulum (ER) in all presynaptic terminals. However, the precise role of the ER in modifying STP remains unexplored. We performed in-silico experiments in synaptic geometries based on reconstructions of the rat CA3-CA1 synapses to investigate the contribution of ER. Our model predicts that presynaptic ER is critical in generating themore »observed short-term plasticity profile of CA3-CA1 synapses and allows synapses with low release probability to operate more reliably. Blocking the ER lowers facilitation in a manner similar to what has been previously characterized in animal models of Alzheimer’s disease and underscores the important role played by presynaptic stores in normal function.« less
    Free, publicly-accessible full text available December 1, 2022
  5. Acinar to ductal metaplasia (ADM) occurs in the pancreas in response to tissue injury and is a potential precursor for adenocarcinoma. The goal of these studies was to define the populations arising from genetically wild type ADM, the associated transcriptionalchanges, and to identify markersof disease progression. Acinar cells were lineage-traced with enhanced yellow fluorescent protein (EYFP)to follow their fate upon injury. Transcripts of over 13,000 EYFP+ cells were determined using single-cellRNA sequencing (scRNA-seq). Single-celltrajectories were generated. Data were compared to gastric metaplasia and human pancreatitis. Results were confirmed by immunostaining and electron microscopy. Surgical specimens of chronic pancreatitis from 15more »patients were evaluatedby immunostaining. scRNA-seq of ADM revealed emergence of a mucin/ductal population (Muc6+, Tff2+) resembling gastric pyloric, gland-base cells. Lineage trajectories suggest that this pyloric metaplasia is an intermediate cell identity between acinar cells and the generation of metaplastic tuft and enteroendocrine cells (EECs). 3-D electron microscopy demonstrates that all identified lineages populate ADM lesions. EECs exhibit substantial heterogeneity, including emergence of enterochromaffin (5-HT+) and delta (SST+) cells. Human pancreatitis shows a similar pyloric metaplasia phenotype anda conserved transcriptional program. Under conditions of chronic injury, acinar cells undergo pyloric metaplasia to mucinous progenitor-like populations, some of which can then seed disparate tuft cell and EEC lineages. EEC subtypes are diverse with the potential to direct disease progression. This program is conserved in human pancreatitis, providing insightinto early events in pancreasdiseases.« less
  6. Long-term potentiation (LTP) is a cellular mechanism of learning and memory that results in a sustained increase in the probability of vesicular release of neurotransmitter. However, previous work in hippocampal area CA1 of the adult rat revealed that the total number of vesicles per synapse decreases following LTP, seemingly inconsistent with the elevated release probability. Here, electron-microscopic tomography (EMT) was used to assess whether changes in vesicle density or structure of vesicle tethering filaments at the active zone might explain the enhanced release probability following LTP. The spatial relationship of vesicles to the active zone varies with functional status. Tightlymore »docked vesicles contact the presynaptic membrane, have partially formed SNARE complexes, and are primed for release of neurotransmitter upon the next action potential. Loosely docked vesicles are located within 8 nm of the presynaptic membrane where SNARE complexes begin to form. Nondocked vesicles comprise recycling and reserve pools. Vesicles are tethered to the active zone via filaments composed of molecules engaged in docking and release processes. The density of tightly docked vesicles was increased 2 h following LTP compared to control stimulation, whereas the densities of loosely docked or nondocked vesicles congregating within 45 nm above the active zones were unchanged. The tethering filaments on all vesicles were shorter and their attachment sites shifted closer to the active zone. These findings suggest that tethering filaments stabilize more vesicles in the primed state. Such changes would facilitate the long-lasting increase in release probability following LTP.

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  7. Jędrzejewska-Szmek, Joanna (Ed.)