Biology subjects

Trigo, F.

Publications and source records attributed to Trigo, F..

3 recordsLinked to original sources

bioRxiv2026

Synaptic vesicle undocking induces low frequency depression

Synaptic depression is often interpreted as reflecting depletion of the readily releasable pool (RRP) following exocytosis. Such a mechanism predicts little or no depression at low stimulation frequency, as RRP replenishment should then offset the loss of vesicles by exocytosis. Nevertheless, in several types of mammalian central synapses, repetitive presynaptic stimulation at low frequency (< 5 Hz) elicits synaptic depression (low frequency depression, or LFD). In the present work we count the number of synaptic vesicles released at individual active zones to study the RRP and its replenishment during LFD. Contrary to depletion models of synaptic depression, we find that LFD does not depend on previous SV consumption. We find that LFD displays a long recovery time course (tens of seconds) when challenged by isolated stimulations but is immediately reversed by a high frequency train. We suggest that LFD results from undocking, a shift between two classes of synaptic vesicles organized sequentially inside the RRP (replacement vs. docked vesicles) in favor of the upstream (replacement) state. While undocking is apparent hundreds of milliseconds after a stimulation, calcium dependent docking takes only a couple of milliseconds, explaining the fast LFD recovery when stimulating at high frequency. Consistent with the undocking model, we find that double presynaptic stimulations alleviate LFD as they favor vesicular docking and RRP replenishment. Finally, we expand our model to explain how stimulation frequency shapes short-term synaptic depression, changing from depression at low frequency to a facilitation-depression sequence at medium or high frequency trains.

neuroscience↗

bioRxiv2023

A first morphological and electrophysiological characterization of FCs of the mouse cerebellum.

The "feathered" cells of Fananas (FCs) are cerebellar glia of unknown function. Initially described more than a century ago, they have been practically absent from the scientific literature. Here, we combined whole-cell patch-clamp recordings, dye loading and near UV-laser photolysis for a first characterization of FCs in terms of their morphology, electrophysiological properties and glutamate-evoked currents. FCs were identified in cerebellar slices by their small cell bodies located in the molecular layer and stubby processes. Despite a more compact shape compared to Bergmann glia (BGs) FCs had similar membrane resistances and basal currents, suggesting electrical coupling between neighboring glia. Dye filling and pharmacological experiments confirmed homo- and heterotypic gap junction coupling among FCs and BGs. Parallel-fiber stimulation evoked in FCs a slow inward current partially blocked by NBQX, along with superimposed fast (ms) transients. Repetitive stimulations resulted in a rapid desensitization of this AMPA-receptor mediated current, which recovered for stimulation intervals >0.5s. Laser photolysis of MNI-caged glutamate replicated fast inward currents with highest current densities in the distant process. We conclude that FCs respond with fast AMPA currents to local glutamate release, and that they integrate ambient glutamate to a slow inward current. Interestingly, FCs prevail throughout adulthood with markedly different densities among cerebellar lobes. Thus, FCs are not just displaced BGs as previously suggested, but they may have lobule specific functions, both locally and at the circuit level, yet to be uncovered.

neuroscience↗

bioRxiv2020

Loss of erythroblasts in acute myeloid leukemia causes iron redistribution with clinical implications

Acute myeloid leukemia (AML) is a heterogeneous disease with poor prognosis and limited treatment strategies. Determining the role of cell-extrinsic regulators of leukemic cells is vital to gain clinical insights into the biology of AML. Iron is a key extrinsic regulator of cancer but its systemic regulation remains poorly explored in AML. To address this question, we studied iron metabolism in AML patients at diagnosis and mechanisms involved using the syngeneic MLL-AF9-induced AML mouse model. We found that AML is a disorder with a unique iron profile not associated with inflammation or transfusion and characterized by high ferritin, low transferrin, high transferrin saturation (TSAT), and high hepcidin. The increased TSAT in particular, contrasts with observations in other cancer types and in anemia of inflammation. Using the MLL-AF9 mouse model of AML, we demonstrated that leukemic blasts take up iron and that the AML-induced loss of erythroblasts is responsible for iron redistribution and an increase in TSAT. We also show that elevated TSAT at diagnosis is independently associated with increased overall survival in AML and suggest that TSAT may be a relevant prognostic marker in AML.

cancer biology↗