mGluR1 enhances efferent inhibition of inner hair cells in the developing rat cochlea

Abstract

Just before the onset of hearing, the inner hair cells (IHCs) receive inhibitory efferent input from cholinergic medial olivocochlear (MOC) neurons originating in the brainstem. This input may serve a role in the maturation of the ascending (afferent) auditory system by inhibiting spontaneous activity of the IHCs. To investigate the molecular mechanisms regulating these IHC efferent synapses, we combined electrical stimulation of the efferent fibres with patch clamp recordings from the IHCs to measure efferent synaptic strength. By examining evoked responses, we show that activation of metabotropic glutamate receptors (mGluRs) by general and group I-specific mGluR agonists enhances IHC efferent inhibition. This enhancement is blocked by application of a group I mGluR1-specific antagonist, indicating that enhancement of IHC efferent inhibition is mediated by group I mGluRs and specifically by mGluR1s. By comparing spontaneous and evoked responses, we show that group I mGluR agonists act presynaptically to increase neurotransmitter release without affecting postsynaptic responsiveness. Moreover, endogenous glutamate released from the IHCs also enhances IHC efferent inhibition via the activation of group I mGluRs. Finally, immunofluorescence analysis indicates that the efferent terminals are sufficiently close to IHC glutamate release sites to allow activation of mGluRs on the efferent terminals by glutamate spillover. Together, these results suggest that glutamate released from the IHCs activates group I mGluRs (mGluR1s), probably present on the efferent terminals, which, in turn, enhances release of acetylcholine and inhibition of the IHCs. Thus, mGluRs establish a local negative feedback loop positioned to regulate IHC activity and maturation of the ascending auditory system in the developing cochlea.

Compartmentalization of antagonistic Ca 2+ signals in developing cochlear hair cells

“…This difference may stem from multiple sources: (i) the higher spatial resolution of EM microscopy that could distinguish closely positioned synapses not resolvable under light microscopy (as indicated in Results, a high proportion of afferent synapses are located at <1 μm from the next nearest afferent, similar to what was observed for efferent-to-efferent separation); (ii) some morphologically identified synapses might not be functional; and, finally, (iii) electrical stimulation might not activate all available fibers of MOC neurons. However, it is important to note that, irrespective of the total number of synapses, the intertwined disposition and close proximity between afferent and efferent synapses observed in both EM and functional imaging were striking and in accordance with previously estimated values (42,43).…”

Altered cochlear innervation in developing and mature naked and Damaraland mole rats

“…To quantify the degree of developmental retraction, the distance between each afferent ribbon (CTBP2 immunopunctum) and its nearest efferent terminal (synapsin immunopunctum) was quantified as described previously (Sadeghi et al, ; Ye et al, ). We predicted that this distance would increase with development.…”

“…Custom script developed in R was used to calculate Euclidean distances between immunopuncta (as described previously in Sadeghi, Pyott, Yu, & Glowatzki, ; Ye, Goutman, Pyott, & Glowatzki, ) and to classify inner hair cell (IHC) afferent ribbons (CTBP2 immunopuncta) as either pillar or modiolar. Briefly, for this later analysis, x , y , and z coordinates were determined for the afferent ribbons and the nuclei using the spots function in Imaris.…”

Distribution of Kv3 Subunits in Cochlear Afferent and Efferent Nerve Fibers Implies Distinct Role in Auditory Processing

“…Not surprisingly, neurotransmitter release from cochlear efferent fiber axons are modulated by multiple mechanisms [55,56]. Metabotropic glutamate receptor, voltage gated Ca 2+ channels and Ca 2+ -activated BK K + channel at the presynaptic efferent fiber axons had been reported to contribute to the efferent synaptic transmission [56][57][58]. Here, based on our finding of K v 3.4 at the MOC and LOC efferent fiber axons, we propose to add K v 3.4 to the list of proteins modulating cochlear efferent neurotransmitter release.…”