Biology subjects

Sprengel, R.

Publications and source records attributed to Sprengel, R..

6 recordsLinked to original sources

bioRxiv2025

Aetokthonotoxin, the causative agent of vacuolar myelinopathy, uncouples oxidative phosphorylation due to protonophore activity

Aetokthonotoxin (AETX) is an emerging environmental toxin produced by the freshwater cyanobacterium Aetokthonos hydrillicola. Accumulating in the food chain, it causes vacuolar myelinopathy, a neurological disease affecting a wide range of wildlife characterized by the development of large intra-myelinic vacuoles in the white matter of the brain. So far, the mode of action of AETX is unknown. After discovering that AETX is cytostatic and arrests cancer cell lines in G1-phase, metabolomic profiling of AETX-treated cells as well as an assessment of the physico-chemical properties of the compound suggested that AETX is a weakly acidic uncoupler of mitochondrial respiration. We confirmed this hypothesis by in vitro assays on mammalian cells, finding that AETX has the expected effects on the mitochondrial network morphology, mitochondrial membrane potential, and oxygen consumption rates, resulting in affected ATP generation. We confirmed that AETX is capable of transporting protons across lipid bilayers. In summary, we demonstrate that AETX is a protonophore that uncouples oxidative phosphorylation in mitochondria, the primary event of AETX intoxication. Significance statementAetokthonotoxin (AETX) is an emerging cyanotoxin. Produced by the cyanobacterium Aetokthonos hydrillicola, it is transferred through the food chain, affects the nervous system, and eventually causes mortality in animals of various taxa. Our finding that AETX is an unspecific uncoupler of mitochondrial respiration implies that it might also be harmful for human health upon ingestion and trophic accumulation. First steps towards a full risk assessment are needed. An important aspect in this regard is the elucidation of the toxins mode of action. We anticipate our findings to be a starting point for the development of an adverse outcome pathway addressing the formation of vacuolar myelinopathy, expanding the significance of our results to the future risk assessment of other environmental neurotoxins.

pharmacology and toxicology↗

bioRxiv2021

Glutamatergic dysfunction leads to a hyper-dopaminergic phenotype through deficits in short-term habituation: a mechanism for aberrant salience.

Psychosis in disorders like schizophrenia is commonly associated with aberrant salience and elevated striatal dopamine. However, the underlying cause(s) of this hyper-dopaminergic state remain elusive. Various lines of evidence point to glutamatergic dysfunction and impairments in synaptic plasticity in the aetiology of schizophrenia, including deficits associated with the GluA1 AMPAR subunit. GluA1 knockout (Gria1-/-) mice provide a model of impaired synaptic plasticity in schizophrenia and exhibit a selective deficit in a form of short-term memory which underlies short-term habituation. As such, these mice are unable to reduce attention to recently presented stimuli. In this study we used fast-scan cyclic voltammetry to measure phasic dopamine responses in the nucleus accumbens of Gria1-/- mice to determine whether this behavioral phenotype might be a key driver of a hyper-dopaminergic state. There was no effect of GluA1 deletion on electrically-evoked dopamine responses in anaesthetized mice, demonstrating normal endogenous release properties of dopamine neurons in Gria1-/- mice. Furthermore, dopamine signals were initially similar in Gria1-/- mice compared to controls in response to both sucrose rewards and neutral light stimuli. They were also equally sensitive to changes in the magnitude of delivered rewards. In contrast, however, these stimulus-evoked dopamine signals failed to habituate with repeated presentations in Gria1-/- mice, resulting in a task-relevant, hyper-dopaminergic phenotype. Thus, here we show that GluA1 dysfunction, resulting in impaired short-term habituation, is a key driver of enhanced striatal dopamine responses, which may be an important contributor to aberrant salience and psychosis in psychiatric disorders like schizophrenia.

neuroscience↗

bioRxiv2020

Membrane Ca2+ permeability and IP3R2 dependent Ca2+-induced Ca2+ release are essential for astrocytic intracellular Ca2+ elevation upon neuronal stimulation at the mouse hippocampal CA3 - CA1 excitatory synapses

Astrocytes are intricately involved in the activity of neural circuits, however, their basic physiology of interacting with neurons remains controversial. Using dual-indicator two-photon imaging of neurons and astrocytes during stimulations of hippocampal CA3 - CA1 Schaffer collateral (Scc) excitatory synapses, we report that under physiological conditions, the increased glutamate released from the higher frequency stimulation of neurons can accelerate local astrocytic Ca2+ levels. As consequences of extracellular glutamate clearance and maintaining of astrocytic intracellular Na+ homeostasis, the increase of astrocytic membrane Ca2+ permeability via Na+/Ca2+ exchanger (NCX) reverse mode is the primary reason of eliciting astrocytic intracellular Ca2+ elevation upon neuronal stimulation. This Ca2+-induced Ca2+ release is dependent on inositol triphosphate receptor type 2 (IP3R2). In addition, ATP released from Scc excitatory synapses can contribute to this molecular mechanism of Ca2+-induced Ca2+ release in astrocytes.

neuroscience↗

bioRxiv2019

Ca2+ signaling in astrocytes is sleep-wake state specific and modulates sleep

Astrocytic Ca2+ signaling has been intensively studied in health and disease but remains uncharacterized in sleep. Here, we employed a novel activity-based algorithm to assess astrocytic Ca2+ signals in the barrel cortex of awake and naturally sleeping mice while monitoring neuronal Ca2+ activity, brain rhythms and behavior. We discovered that Ca2+ signaling in astrocytes exhibits distinct features across the sleep-wake cycle and is reduced in sleep compared to wakefulness. Moreover, an increase in astrocytic Ca2+ signaling precedes transitions from slow-wave sleep to wakefulness, with a peak upon awakening exceeding the levels during whisking and locomotion. Genetic ablation of a key astrocytic Ca2+ signaling pathway resulted in fragmentation of slow-wave sleep, yet increased the frequency of sleep spindles. Our findings suggest a role for astrocytic Ca2+ signaling in modulating sleep.

neuroscience↗

bioRxiv2019

retroLEAP: rAAV-based retrograde trans-synaptic labeling, expression and perturbation

Identifying and manipulating synaptically connected neurons across brain regions remains a core challenge in understanding complex nervous systems. RetroLEAP is a novel approach for retrograde trans-synaptic Labelling, Expression And Perturbation. GFP-dependent recombinase (Flp-DOG) detects trans-synaptic transfer of GFP-tetanus toxin heavy chain fusion protein (GFP-TTC) and activates expression of any gene of interest in synaptically connected cells. RetroLEAP overcomes existing limitations, is non-toxic, highly flexible, efficient, sensitive and easy to implement.

neuroscience↗

bioRxiv2018

Dissociating time and number in reinforcement rate learning

Animals are highly sensitive to the temporal properties of predictive cues 1, a feature of learning unexplained by traditional trial-based associative theories of learning 2-4. It has been proposed that animals symbolically encode temporal durations in order to extract statistical information about events, such as the reinforcement rate during a cues presentation 5,6. Thus, long-duration cues elicit weaker responding than short-duration cues ( cue duration effect), because they signal a lower rate of reinforcement 7,8. An alternative, simple account is that time-dependent changes in stimulus processing, such as short-term habituation, lead to the effect of cue duration on learning 9,10, with attention decreasing throughout the duration of a cue, limitin ...

animal behavior and cognition↗