Biology subjects

Wedemeyer, C.

Publications and source records attributed to Wedemeyer, C..

5 recordsLinked to original sources

bioRxiv2026

Medial Olivocochlear Activity Modulates Central Auditory Synapse Structure and Function

In many mammals, the auditory system is immature at birth and undergoes activity-dependent refinement. The medial olivocochlear system (MOC) contributes to the maturation of central auditory connectivity by shaping spontaneous activity in the developing inner ear. Although altered MOC activity has been linked to electrical and synaptic dysfunctions in different central auditory nuclei, an in-depth analysis of the same synapse under conditions of absent versus enhanced MOC activity is lacking. In this work, we set out a physiological and structural analysis of the calyx of Held and the principal neurons of the medial nucleus of the trapezoid body (CH-MNTB) synapse at postnatal days 12-14 in three mouse models of either sex: wild-type (WT), 9 knock-in (9KI; with enhanced MOC activity), and 9 knock-out (9KO; which lacks MOC activity). Electrophysiological recordings in brain slices revealed a reduced synaptic strength efficacy in 9KI compared to WT, including smaller excitatory postsynaptic current (EPSC) amplitudes, stronger short-term depression during repetitive stimulation and a decrease readily releasable pool size. In contrast, 9KO mice showed minimal synaptic differences relative to WT. Serial block-face electron microscopy (SBEM) reconstructions demonstrated morphological alterations of the CH in both MOC-manipulated mouse models. However, 9KI mice exhibited the largest deviations, including fewer morphologically complex CHs and increased poly-innervation of MNTB cells. These results indicate that transient, well-regulated efferent control of cochlear activity is crucial for establishing accurate central auditory connectivity. Moreover, the enhancement of MOC activity drives more pronounced developmental changes in brainstem auditory circuitry than its absence. Significance StatementBefore hearing onset, inner hair cells in altricial mammals show spontaneous electrical activity crucial for proper auditory pathway development. This activity is finely regulated by descending efferent nerves from the central nervous system during a critical developmental period, ensuring precise auditory circuit formation. Our study shows that genetically manipulating efferent function --either by eliminating it or enhancing it-- leads to structural alterations and severe synaptic dysfunction within the auditory brainstem. These results indicate that transient, well-regulated efferent control of cochlear activity is crucial for establishing accurate central auditory connectivity. Importantly, enhancing efferent peripheral activity causes more pronounced central synaptic changes than its absence, highlighting the importance of balanced efferent modulation during early auditory system development for normal brainstem auditory function.

neuroscience↗

bioRxiv2024

Co-release of GABA and ACh from medial olivocochlear neurons fine tunes cochlear efferent inhibition

During development, inner hair cells (IHCs) in the mammalian cochlea are unresponsive to acoustic stimuli but instead exhibit spontaneous activity. During this same period, neurons originating from the medial olivocochlear complex (MOC) transiently innervate IHCs, regulating their firing pattern which is crucial for the correct development of the auditory pathway. Although the MOC-IHC is a cholinergic synapse, previous evidence indicates the widespread presence of gamma-aminobutyric acid (GABA) signaling markers, including presynaptic GABAB receptors (GABABR). In this study, we explore the source of GABA by optogenetically activating either cholinergic or GABAergic fibers. The optogenetic stimulation of MOC terminals from GAD;ChR2-eYFP and ChAT;ChR2-eYFP mice evoked synaptic currents in IHCs that were blocked by -bungarotoxin. This suggests that GABAergic fibers release ACh and activate 910 nicotinic acetylcholine receptors (nAChRs). Additionally, MOC cholinergic fibers release not only ACh but also GABA, as the effect of GABA on ACh response amplitude was prevented by applying the GABAB-R blocker (CGP 36216). Using optical neurotransmitter detection and calcium imaging techniques, we examined the extent of GABAergic modulation at the single synapse level. Our findings suggest heterogeneity in GABA modulation, as only 15 out of 31 recorded synaptic sites were modulated by applying the GABABR specific antagonist, CGP (100-200 {micro}M). In conclusion, we provide compelling evidence that GABA and ACh are co-released from at least a subset of MOC terminals. In this circuit, GABA functions as a negative feedback mechanism, locally regulating the extent of cholinergic inhibition at certain efferent-IHC synapses during an immature stage. Significance statementBefore hearing onset, the medial olivocochlear (MOC) efferent system of the mammalian cochlea regulates the pattern of IHC spontaneous firing rate through the activation of 910 nAChRs. However, GABA is also known to have a modulatory role at the MOC-IHC synapse. Our results show that GABA is co-released from at least a subset of MOC terminals, working as a precise regulatory mechanism for ACh release. Furthermore, we demonstrate that not all synaptic contacts within a single IHC are equally modulated by GABA.

physiology↗

bioRxiv2024

GABAergic synapses between auditory efferent neurons and type II spiral ganglion afferent neurons in the mouse cochlea

Cochlear outer hair cells (OHCs) are electromotile and are implicated in mechanisms of amplification of responses to sound that enhance sound sensitivity and frequency tuning. They send information to the brain through glutamatergic synapses onto a small subpopulation of neurons of the ascending auditory nerve, the type II spiral ganglion neurons (SGNs). The OHC synapses onto type II SGNs are sparse and weak, suggesting that type II SGNs respond primarily to loud and possibly damaging levels of sound. OHCs also receive innervation from the brain through the medial olivocochlear (MOC) efferent neurons. MOC neurons are cholinergic yet exert an inhibitory effect on auditory function as they are coupled to alpha9/alpha10 nicotinic acetylcholine receptors (nAChRs) on OHCs, which leads to calcium influx that gates SK potassium channels. The net hyperpolarization exerted by this efferent synapse reduces OHC activity-evoked electromotility and is implicated in cochlear gain control, protection against acoustic trauma, and attention. MOC neurons also label for markers of gamma-aminobutyric acid (GABA) and GABA synthesis. GABAB autoreceptor (GABABR) activation by GABA released from MOC terminals has been demonstrated to reduce ACh release, confirming important negative feedback roles for GABA. However, the full complement of GABAergic activity in the cochlea is not currently understood, including the mechanisms that regulate GABA release from MOC axon terminals, whether GABA diffuses from MOC axon terminals to other postsynaptic cells, and the location and function of GABAA receptors (GABAARs). Previous electron microscopy studies suggest that MOC neurons form contacts onto several other cell types in the cochlea, but whether these contacts form functional synapses, and what neurotransmitters are employed, are unknown. Here we use immunohistochemistry, optical neurotransmitter imaging and patch-clamp electrophysiology from hair cells, afferent dendrites, and efferent axons to demonstrate that in addition to presynaptic GABABR autoreceptor activation, MOC efferent axon terminals release GABA onto type II SGN afferent dendrites with postsynaptic activity mediated by GABAARs. This synapse may have multiple roles including developmental regulation of cochlear innervation, fine tuning of OHC activity, or providing feedback to the brain about MOC and OHC activity. Significance StatementCochlear OHCs receive efferent feedback from the brainstem to regulate auditory sensitivity and send afferent, feedforward information to the brain via type II SGNs. Histological evidence suggests an abundance of additional synaptic contacts in the OHC region, although neurotransmission at these synapses has not been determined. Here we demonstrate a synapse between efferent and afferent neurons that bypasses OHCs, and functions via GABAAR signaling. Although the function of this synapse is unknown, it is activity-dependent and persists in the mature cochlea, suggesting a role in auditory function.

neuroscience↗

bioRxiv2018

Developmental synaptic changes at the transient olivocochlear-inner hair cell synapse

In the mature mammalian cochlea, inner hair cells (IHCs) are mainly innervated by afferent fibers that convey sound information to the central nervous system. During postnatal development, however, medial olivocochlear (MOC) efferent fibers transiently innervate the IHCs. The MOC-IHC synapse, functional from postnatal day (P)0 to hearing onset (P12), undergoes dramatic changes in the sensitivity to acetylcholine (ACh) and in the expression of key postsynaptic proteins. To evaluate whether there are associated changes in the properties of ACh release during this period, we used a cochlear preparation from mice at P4, P6-7 and P9-11 and monitored transmitter release from MOC terminals in voltage-clamped IHCs in the whole-cell configuration. The quantum content increased 5.6x from P4 to P9-11 due to increases in the size and replenishment rate of the readily releasable pool (RRP) of synaptic vesicles, without changes in their probability of release (Pvesicle) or quantum size. This strengthening in transmission was accompanied by changes in the short-term plasticity (STP) properties, which switched from facilitation at P4 to depression at P9-11. We have previously shown that at P9-11, ACh release is supported by P/Q and N-type voltage-gated calcium channels (VGCCs) and negatively regulated by BK potassium channels activated by Ca2+ influx through L-type VGCCs. We now show that at P4 and P6-7, release is mediated by P/Q-, R- and L-type VGCCs. Interestingly, L-type VGCCs have a dual role: they both support release and fuel BK channels, suggesting that at immature stages the presynaptic proteins involved in release are less compartmentalized.\n\nSignificance statementDuring postnatal development prior to the onset of hearing, cochlear IHCs present spontaneous Ca2+ action potentials which release glutamate at the first auditory synapse in the absence of sound stimulation. The IHC Ca2+ action potential frequency pattern, which is crucial for the correct establishment and function of the auditory system, is regulated by the efferent MOC system that transiently innervates IHCs during this period. We show short-term synaptic plasticity properties of the MOC-IHC synapse that tightly shape this critical developmental period.

neuroscience↗

bioRxiv2018

Strengthening of the efferent olivocochlear system leads to synaptic dysfunction and tonotopy disruption of a central auditory nucleus

The auditory system in many mammals is immature at birth but precisely organized in adults. Spontaneous activity in the inner ear plays a critical role in guiding this process. This is shaped by an efferent pathway that descends from the brainstem and makes transient direct synaptic contacts with inner hair cells (IHCs). In this work, we used an 9 cholinergic receptor knock-in mouse model (of either sex) with enhanced medial efferent activity (Chrna9L9T, L9T) to understand the role of the olivocochlear system in the correct establishment of auditory circuits. Wave III of auditory brainstem responses (which represents synchronized activity of synapses within the superior olivary complex) were smaller in L9T mice, suggesting a central dysfunction. The mechanism underlying this functional alteration was analysed in brain slices containing the medial nucleus of the trapezoid body (MNTB), where neurons are topographically organized along a medio-lateral axis. The topographic organization of MNTB physiological properties observed in WT mice was abolished in the L9T mice. Additionally, electrophysiological recordings in slices evidenced MNTB synaptic alterations, which were further supported by morphological alterations. The present results suggest that the transient cochlear efferent innervation to IHCs during the critical period before the onset of hearing is involved in the refinement of topographic maps as well as in setting the correct synaptic transmission at central auditory nuclei.\n\nSignificance StatementCochlear inner hair cells of altricial mammals display spontaneous electrical activity before hearing onset. The pattern and firing rate of these cells is crucial for the correct maturation of the central auditory pathway. A descending efferent innervation from the central nervous system contacts hair cells during this developmental window. The function of this transient efferent innervation remains an open question. The present work shows that the genetic enhancement of efferent function disrupts the orderly topographic distribution at the medial nucleus of the trapezoid body level and causes severe synaptic dysfunction. Thus, the transient efferent innervation to the cochlea is necessary for the correct establishment of the central auditory circuitry.

neuroscience↗