Biology subjects

Nerlich, J.

Publications and source records attributed to Nerlich, J..

6 recordsLinked to original sources

bioRxiv2026

Presynaptic GABAA Receptors Mediate Ethanol-Induced Suppression at a Central Auditory Synapse

Acute alcohol consumption impairs speech perception, particularly in noisy environments, but the synaptic mechanisms underlying this auditory deficit remain unknown. Here, we investigated how low-dose ethanol modulates the endbulb of Held synapse in the Mongolian gerbil cochlear nucleus, the first central relay of the auditory pathway. In vivo recordings showed that ethanol suppresses sound-evoked firing, an effect blocked by GABAA receptor antagonists. Direct presynaptic patch-clamp recordings revealed that ethanol potentiates GABAA currents at the endbulb of Held terminal but not at the postsynaptic spherical bushy cell. A high intra-terminal chloride concentration drives a GABA-mediated depolarization that activates low-threshold Kv1 potassium channels and shunts the presynaptic action potential. The reduced action potential amplitude limits calcium influx and glutamate release, effectively suppressing synaptic transmission. These findings identify ethanol-enhanced presynaptic shunting inhibition at the first central auditory synapse as a cellular mechanism for alcohol-induced auditory dysfunction.

neuroscience↗

bioRxiv2025

Unreliable homeostatic action potential broadening in cultured dissociated neurons

Homeostatic plasticity preserves neuronal activity against perturbations. Recently, somatic action potential broadening was proposed as a key homeostatic adaptation to chronic inactivity in neocortical neurons. Since action potential shape critically controls calcium entry and neuronal function, broadening provides an attractive homeostatic feedback mechanism to regulate activity. Here, we report that chronic inactivity induced by sodium channel block does not broaden action potentials in neocortical neurons under a wide range of conditions. In contrast, action potentials were broadened in CA3 neurons of organotypic hippocampal cultures by chronic sodium channel block and in hippocampal dissociated cultures by chronic synaptic block. Mechanistically, BK-type potassium channels were proposed to underly inactivity-induced action potential broadening. However, BK channels did not affect action potential duration in our recordings. Our results indicate that action potential broadening can occur in specific neurons and conditions but is not a general mechanism of homeostatic plasticity in cultured neurons.

neuroscience↗

bioRxiv2024

Multi-behavioral phenotyping in zebrafish identifies a novel disruptor of non-associative learning with environmental and human relevance

BackgroundThe vertebrate nervous system is vulnerable to chemical toxicity and the widespread release of chemicals into the environment outstrips the capacity to assess their safety. The zebrafish (Danio rerio) is a powerful vertebrate model that can bridge the gap between in vitro and mammalian-based in vivo studies. However, the behavior-rich repertoire of larval zebrafish, a 3R-compliant model amenable to higher-throughput chemical screens, has yet to be fully deployed to identify and characterize chemical compounds that cause neurotoxicity. ObjectiveWe sought to establish a multi-behavioral phenotyping approach in larval zebrafish to identify and mechanistically elucidate neuroactive chemicals, with particular focus on chemical compounds that affect non-associative habituation learning. MethodsWe devised a battery of automated behavior assays in larval zebrafish. The battery captures stereotypical visual and acoustic behaviors including habituation, a form of non-associative learning. To elucidate mechanisms underlying exposure-induced behavioral alterations in zebrafish, in silico target predictions, pharmacological interventions, patch-clamp recordings in cultured mouse cortical neurons, and human multi-neurotransmitter (hMNR) assay in 3D BrainSpheres were used. ResultsKnown pharmacological modulators of habituation in zebrafish evoked distinct behavioral patterns. By screening chemicals positive for ex vivo N-methyl-D-aspartate receptor (NMDAR) modulation, we identified chlorophene, a biocide that caused sedation, paradoxical excitation, and reduced habituation in zebrafish. Using in silico target predictions and pharmacological interventions, we discovered that chlorophene acts via gamma-aminobutyric acid A receptors (GABAARs), a previously unknown target site. Orthogonal validation in cultured mouse cortical neurons and human stem cell-derived BrainSpheres confirmed chlorophenes interaction with GABAARs. Chlorophenes behavioral profile resembled that of flupirtine, a Kv7 potassium channel (M-current) activator, suggesting that habituation deficits stem from M-current rather than GABAAR modulation. ConclusionsThese studies combined a series of behavior assays in a phenotypically rich, rapid, and inexpensive non-mammalian vertebrate test system to screen chemicals for neurotoxicity. Together with in silico target predictions and mouse- and human-based models, our findings establish multi-behavioral phenotyping in zebrafish as a powerful toolkit for neurotoxicity testing and mechanism identification, with relevance for humans.

pharmacology and toxicology↗

bioRxiv2023

Rab3 mediates cyclic AMP-dependent presynaptic plasticity and olfactory learning

Presynaptic forms of plasticity occur throughout the nervous system and play an important role in learning and memory but the underlying molecular mechanisms are insufficiently understood. Here we show that the small GTPase Rab3 is a key mediator of cyclic AMP (cAMP)-induced presynaptic plasticity in Drosophila. Pharmacological and optogenetic cAMP production triggered concentration-dependent alterations of synaptic transmission, including potentiation and depression of evoked neurotransmitter release, as well as strongly facilitated spontaneous release. These changes correlated with a nanoscopic rearrangement of the active zone protein Unc13A and required Rab3. To link these results to animal behaviour, we turned to the established role of cAMP signalling in memory formation and demonstrate that Rab3 is necessary for olfactory learning. As Rab3 is dispensable for basal synaptic transmission, these findings highlight a molecular pathway specifically dedicated to tuning neuronal communication and adaptive behaviour.

neuroscience↗

bioRxiv2023

Fully-primed slowly-recovering vesicles mediate presynaptic LTP at neocortical neurons

Pre- and postsynaptic forms of long-term potentiation (LTP) are candidate synaptic mechanisms underlying learning and memory. At layer 5 pyramidal neurons LTP increases the initial synaptic strength but also short-term depression during high-frequency transmission. This classical form of presynaptic LTP has been referred to as redistribution of synaptic efficacy. However, the underlying mechanisms remain unclear. We therefore performed whole-cell recordings from layer 5 pyramidal neurons in acute cortical slices of rats and analyzed presynaptic function before and after LTP induction by paired pre- and postsynaptic neuronal activity. LTP was successfully induced in about half of the synaptic connections tested and resulted in increased synaptic depression during high-frequency transmission and a decelerated recovery from depression due to an increased occurrence of a slow recovery component. Analysis with a recently established sequential two-step vesicle priming model indicates an increase in the abundance of fully-primed and slowly-recovering vesicles. A systematic analysis of short-term plasticity and synapse-to-synapse variability of synaptic strength at various types of synapses revealed that stronger synapses generally recover more slowly from synaptic depression. Finally, pharmacological stimulation of the cyclic adenosine monophosphate (cAMP) and diacylglycerol (DAG) signaling pathways, which are both known to promote synaptic vesicle priming mimicked electrically-induced LTP and slowed the recovery from depression. Our data thus demonstrate that LTP at layer 5 pyramidal neurons increases synaptic strength primarily by enlarging a subpool of fully-primed slowly-recovering vesicles.

neuroscience↗

bioRxiv2022

NMDA-receptor-Fc-fusion constructs neutralize anti- NMDA receptor antibodies

N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most common subtype of autoimmune encephalitis characterized by a complex neuropsychiatric syndrome ranging from memory impairment and psychosis to coma. Patients develop an intrathecal immune response against NMDARs with antibodies that presumably bind to the amino-terminal domain (ATD) of the GluN1 subunit. The therapeutic response to immunotherapy is often delayed and does not directly interfere with intrathecal synthesis of pathogenic antibodies. Therefore, new therapeutic approaches for fast neutralization of NMDAR antibodies are needed. Here, we developed fusion constructs consisting of the Fc part of immunoglobulin G and the ATDs of either GluN1 or GluN2B or both, GluN1 and GluN2B, subunits. Surprisingly, both subunits were required to generate high-affinity epitopes. The construct with both subunits efficiently prevented NMDAR binding of patient-derived monoclonal antibodies and of patient cerebrospinal fluid containing high-titer NMDAR antibodies. Furthermore, it inhibited the internalization of NMDARs in rodent dissociated neurons and human induced pluripotent stem cells (iPSC)-derived neurons. Finally, the construct stabilized NMDAR currents recorded in rodent neurons. Our results demonstrate that both GluN1 and GluN2B subunits contribute to the main immunogenic region of the NMDAR and provide a promising strategy for fast and specific treatment of NMDAR encephalitis, which can complement immunotherapy.

neuroscience↗