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 ∼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 ∼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 highlevel sound.

Noise induced reversible changes of cochlear ribbon synapses contribute to temporary hearing loss in mice

“…A previous study proposed that synaptic loss could not recover by 8 weeks post-exposure, despite recovery of ABR thresholds at 1-2 weeks post-exposure [15]. Different from this report, our study shows that maximal loss of ribbon synapse occurred on the 4 th day and that complete recovery of synaptic loss was achieved within 2 weeks after noise exposure.…”

A mouse model for visualization of GABAB receptors

“…This is consistent with a prejunctional inhibitory role for GABA B receptors in modulating ileal contraction, via actions within the enteric nervous system (Sanger et al, 2002). The GB1 2/2 , BAC 1/1 mice recently also allowed us to localize GABA B receptors in cochlear neurons (Maison et al, 2009). This shows that these mice represent a useful tool to identify GABA B receptors in cells that are not yet linked to GABA B receptor physiology.…”

Increased GABAB Receptor-Mediated Signaling Reduces the Susceptibility of Fragile X Knockout Mice to Audiogenic Seizures

“…Several brain regions implicated in the development and progression of auditory seizures in rodents, including the cochlea, inferior and superior colliculus, and periaqueductal gray, express mGluR5, GABA B receptors, and/or RGS4 (Romano et al, 1995;Gold et al, 1997;Margeta-Mitrovic et al, 1999;Ross and Coleman, 2000;Friedland et al, 2006;Maison et al, 2009). We propose that in the auditory pathways involved in seizure induction and progression, auditory signals are balanced by mGluR (activating) and GABA B receptor (suppressing) signaling (Fig.…”