Biology subjects

Keine, C.

Publications and source records attributed to Keine, C..

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↗

bioRxiv2026

Presynaptic CaV2.1 calcium dependent facilitation is essential for faithful auditory information transfer

Activity-dependent modulation of presynaptic voltage-gated Ca2+ channels (CaV2) regulates Ca2+ influx to control neuronal circuit output. Although CaV2.1 can undergo robust Ca2+ dependent facilitation (CDF), whether it occurs in native central nervous system neuronal circuits is disputed. Accurate auditory information processing requires precise and reliable synaptic transmission at high activity rates in the auditory brainstem. To determine if CaV2.1 CDF is a key regulator of high-fidelity synaptic transmission, we expressed CaV2.1 splice variants capable (CaV2.1 37a) or incapable (CaV2.1 37b) of CDF at the calyx of Held presynaptic terminal in the auditory brainstem. We found no difference in basal CaV2.1 currents or synaptic transmission. However, CaV2.1 37b terminals lacked CDF, synaptic facilitation and had a decreased reliability and precision of postsynaptic action-potential firing. Additionally, the Wave III amplitude of the auditory brainstem responses was reduced. We propose that CaV2.1 CDF is essential for accurate auditory information processing.

neuroscience↗

bioRxiv2025

Variation in Synaptic Inputs Drives Functional Versatility for Sound Encoding in Globular Bushy Cells

Synaptic convergence is fundamental to neuronal circuit function, underpinning computations such as coincidence detection and signal integration. Across sensory systems, convergence architecture and synaptic input strengths are key for extracting stimulus features and processing of sensory information. In the cochlear nucleus, globular bushy cells (GBCs) receive convergent inputs from multiple auditory nerve fibers via large endbulb of Held terminals. While these inputs vary considerably in size, even among those targeting the same cell, the functional consequences of this variation for sound encoding remain unclear. Here, we investigated how synaptic input variation shapes sound encoding in GBCs of Mongolian gerbils using in vitro conductance-clamp recordings and computational modeling. By simulating synaptic inputs with variable strength distributions, we found that increasing input variation enhances rate coding at the expense of temporal precision. These findings suggest that endbulb strength heterogeneity allows the GBC population to operate along a functional continuum, generating diverse information streams to downstream targets.

neuroscience↗

bioRxiv2022

Presynaptic Rac1 controls synaptic strength through the regulation of synaptic vesicle priming.

Synapses contain a limited number of synaptic vesicles (SVs) that are released in response to action potentials (APs). Therefore, sustaining synaptic transmission over a wide range of AP firing rates and timescales depends on SV release and replenishment. Although actin dynamics impact synaptic transmission, how presynaptic regulators of actin signaling cascades control SV release and replenishment remains unresolved. Rac1, a Rho GTPase, regulates actin signaling cascades that control synaptogenesis, neuronal development, and postsynaptic function. However, the presynaptic role of Rac1 in regulating synaptic transmission is unclear. To unravel Rac1s roles in controlling transmitter release, we performed selective presynaptic ablation of Rac1 at the mature mouse calyx of Held synapse. Loss of Rac1 increased synaptic strength, accelerated EPSC recovery after conditioning stimulus trains, and augmented spontaneous SV release with no change in presynaptic morphology or AZ ultrastructure. Analyses with constrained short-term plasticity models revealed faster SV priming kinetics and, depending on model assumptions, elevated SV release probability or higher abundance of tightly docked fusion-competent SVs in Rac1-deficient synapses. We conclude that presynaptic Rac1 is a key regulator of synaptic transmission and plasticity mainly by regulating the dynamics of SV priming and potentially SV release probability.

neuroscience↗

bioRxiv2019

Presynaptic mitochondria volumes and complexity of subsynaptic distribution increase during development at a high-fidelity synapse

The calyx of Held, a large glutamatergic presynaptic terminal in the auditory brainstem undergoes developmental changes to support the high action-potential firing rates required for auditory information encoding. In addition, calyx terminals are morphologically diverse which impacts vesicle release properties and synaptic plasticity. Mitochondria influence synaptic plasticity through calcium buffering and are crucial for providing the energy required for synaptic transmission. Therefore, it has been postulated that mitochondrial levels increase during development and contribute to the morphological-functional diversity in the mature calyx. However, the developmental profile of mitochondrial volumes and subsynaptic distribution at the calyx of Held remains unclear. To provide insight on this, we developed a helper-dependent adenoviral vector (HdAd) that expresses the genetically encoded peroxidase marker for mitochondria, mito-APEX2, at the mouse calyx of Held. We developed protocols to detect labeled mitochondria for use with serial block face scanning electron microscopy to carry out semi-automated segmentation of mitochondria, high-throughput whole terminal reconstruction and presynaptic ultrastructure in mice of either sex. Subsequently, we measured mitochondrial volumes and subsynaptic distributions at the immature postnatal day 7 (P7) and the mature (P21) calyx. We found an increase of mitochondria volumes in terminals and axons from P7 to P21 but did not observe differences between stalk and swelling subcompartments in the mature calyx. Based on these findings, we propose that mitochondrial volumes and synaptic localization developmentally increase to support high firing rates required in the initial stages of auditory information processing.\n\nSignificance StatementElucidating the developmental processes of auditory brainstem presynaptic terminals is critical to understanding auditory information encoding. Additionally, morphological-functional diversity at these terminals is proposed to enhance coding capacity. Mitochondria provide energy for synaptic transmission and can buffer calcium, impacting synaptic plasticity; however, their developmental profile to ultimately support the energetic demands of synapses following the onset of hearing remains unknown. Therefore, we created a helper-dependent adenoviral vector with the mitochondria-targeting peroxidase mito-APEX2 and expressed it at the mouse calyx of Held. Volumetric reconstructions of serial block face electron microscopy data of immature and mature labeled calyces reveal that mitochondrial volumes are increased to support high firing rates upon maturity.

neuroscience↗

bioRxiv2018

Functional connectivity with short-term dynamics explains diverse patterns of excitatory spike transmission in vivo

Information transmission in neural networks is influenced by both short-term synaptic plasticity (STP) as well as non-synaptic factors, such as after-hyperpolarization currents and changes in excitability. Although these effects have been widely characterized in vitro using intracellular recordings, how they interact in vivo is unclear. Here we develop a statistical model of the short-term dynamics of spike transmission that aims to disentangle the contributions of synaptic and non-synaptic effects based only on observed pre- and postsynaptic spiking. The model includes a dynamic functional connection with short-term plasticity as well as effects due to the recent history of postsynaptic spiking and slow changes in postsynaptic excitability. Using paired spike recordings, we find that the model accurately describes the short-term dynamics of in vivo spike transmission at a diverse set of identified and putative excitatory synapses, including a thalamothalamic connection in mouse, a thalamocortical connection in a female rabbit, and an auditory brainstem synapse in a female gerbil. We illustrate the utility of this modeling approach by showing how the spike transmission patterns captured by the model may be sufficient to account for stimulus-dependent differences in spike transmission in the auditory brainstem (endbulb of Held). Finally, we apply this model to large-scale multi-electrode recordings to illustrate how such an approach has the potential to reveal cell-type specific differences in spike transmission in vivo. Although short-term synaptic plasticity parameters estimated from ongoing pre- and postsynaptic spiking are highly uncertain, our results are partially consistent with previous intracellular observations in these synapses. Significance StatementAlthough synaptic dynamics have been extensively studied and modeled using intracellular recordings of post-synaptic currents and potentials, inferring synaptic effects from extracellular spiking is challenging. Whether or not a synaptic current contributes to postsynaptic spiking depends not only on the amplitude of the current, but also on many other factors, including the activity of other, typically unobserved, synapses, the overall excitability of the postsynaptic neuron, and how recently the postsynaptic neuron has spiked. Here we developed a model that, using only observations of pre- and postsynaptic spiking, aims to describe the dynamics of in vivo spike transmission by modeling both short-term synaptic plasticity and non-synaptic effects. This approach may provide a novel description of fast, structured changes in spike transmission.

neuroscience↗