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bioRxiv · 10.1101/2024.08.12.607644

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

Castagnola, T.·Castagna, V. C.·Kitcher, S.·Torres Cadenas, L.·Di Guilmi, M. N.·Gomez Casati, M. E.·Buonfiglio, P. I.·Dalamon, V.·Katz, E.·Elgoyhen, A. B.·Weisz, C.·Goutman, J.·Wedemeyer, C.
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Abstract

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.

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Castagnola, T., Castagna, V. C., Kitcher, S., Torres Cadenas, L., Di Guilmi, M. N., Gomez Casati, M. E., Buonfiglio, P. I., Dalamon, V., Katz, E., Elgoyhen, A. B., Weisz, C., Goutman, J., Wedemeyer, C.. 2024-08-16. Co-release of GABA and ACh from medial olivocochlear neurons fine tunes cochlear efferent inhibition. https://doi.org/10.1101/2024.08.12.607644

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