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Loss of GABAB receptors in cochlear neurons: threshold elevation suggests modulation of outer hair cell function by type II afferent fibers.

ABSTRACT: Despite pharmacological and immunohistochemical evidence for GABA as a neurotransmitter in the olivocochlear efferent bundle, a clear functional role of GABA in the inner ear has not emerged. To explore the role of metabotropic GABA(B) receptors, we characterized the cochlear phenotype of mice with targeted deletion of the GABA(B1) subunit and determined its tissue localization using a mouse line expressing a GFP-tagged GABA(B1) subunit under the endogenous promoter. Immunostaining revealed GABA(B1) expression in both type I and type II ganglion cells and in their synaptic terminals under inner and outer hair cells, respectively. No GABA(B1) expression was observed in hair cells. Mean cochlear thresholds, measured via both auditory brainstem responses and distortion product otoacoustic emissions (DPOAEs), were elevated by approximately 10 dB in GABA(B1)-deficient mice, consistent with outer hair cell dysfunction. Olivocochlear efferent function, assessed via DPOAE suppression during efferent electrical stimulation, was unaffected by GABA(B1) deletion. GABA(B1)-deficient mice showed increased resistance to permanent acoustic injury, with mean threshold shifts approximately 25 dB smaller than wild-types after exposure to 8-16-kHz noise at 100 dB for 2 h. In contrast, there was no vulnerability difference to temporary acoustic injury following exposure to the same noise at 94 dB for 15 min. Our results suggest that GABAergic signaling in type II afferent neurons may be required for normal outer hair cell amplifier function at low sound levels and may also modulate outer hair cell responses to high-level sound.

SUBMITTER: Maison SF

PROVIDER: S-EPMC2644393 | biostudies-other | 2009 Mar

REPOSITORIES: biostudies-other

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Project description:Motoneurons receive thousands of excitatory and inhibitory synapses from descending tracts and primary afferent fibers. The excitability of these neurons must be precisely regulated to respond adequately to the requirements of the environment. In this context, GABAA and GABAB receptors regulate motoneuron synaptic strength. GABAA and GABAB receptors are expressed on primary afferent fibers and motoneurons, while in the descending afferent fibers, only the GABAB receptors are expressed. However, it remains to be known where the GABA that activates them comes from since the GABAergic interneurons that make axo-axonic contacts with primary afferents have yet to be identified in the descending afferent terminals. Thus, the main aim of the present report was to investigate how GABAB receptors functionally modulate synaptic strength between Ia afferent fibers, excitatory and inhibitory descending fibers of the dorsolateral funiculus, and spinal motoneurons. Using intracellular recordings from the spinal cord of the turtle, we provide evidence that the GABAB receptor antagonist, CGP55845, not only prevents baclofen-induced depression of EPSPs but also increases motoneuron excitability and enhances the synaptic strength between the afferent fibers and motoneurons. The last action of CGP55845 was similar in excitatory and inhibitory descending afferents. Interestingly, the action of baclofen was more intense in the Ia primary afferents than in the descending afferents. Even more, CGP55845 reversed the EPSP depression induced by the increased concentration of ambient GABA produced by interneuron activation and GABA transporter blockade. Immunofluorescence data corroborated the expression of GABAB receptors in the turtle’s spinal cord. These findings suggest that GABAB receptors are extrasynaptic and tonically activated on descending afferent fibers and motoneurons by GABA released from astrocytes and GABAergic interneurons in the cellular microenvironment. Finally, our results also suggest that the antispastic action of baclofen may be due to reduced synaptic strength between descending fibers and motoneurons.

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Loss of GABAB receptors in cochlear neurons: threshold elevation suggests modulation of outer hair cell function by type II afferent fibers.

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