Muscarinic Signaling in the Cochlea: Presynaptic and Postsynaptic Effects on Efferent Feedback and Afferent Excitability

Abstract

Acetylcholine is the major neurotransmitter of the olivocochlear efferent system, which provides feedback to cochlear hair cells and sensory neurons. To study the role of cochlear muscarinic receptors, we studied receptor localization with immunohistochemistry and reverse transcription-PCR and measured olivocochlear function, cochlear responses, and histopathology in mice with targeted deletion of each of the five receptor subtypes. M2, M4, and M5 were detected in microdissected immature (postnatal days 10–13) inner hair cells and spiral ganglion cells but not outer hair cells. In the adult (6 weeks), the same transcripts were found in microdissected organ of Corti and spiral ganglion samples. M2 protein was found, by immunohistochemistry, in olivocochlear fibers in both outer and inner hair cell areas. M3 mRNA was amplified only from whole cochleas, and M1 message was never seen in wild-type ears. Auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) were unaffected by loss of Gq-coupled receptors (M1, M3, or M5), as were shock-evoked olivocochlear effects and vulnerability to acoustic injury. In contrast, loss of Gi-coupled receptors (M2 and/or M4) decreased neural responses without affecting DPOAEs (at low frequencies). This phenotype and the expression pattern are consistent with excitatory muscarinic signaling in cochlear sensory neurons. At high frequencies, both ABRs and DPOAEs were attenuated by loss of M2 and/or M4, and the vulnerability to acoustic injury was dramatically decreased. This aspect of the phenotype and the expression pattern are consistent with a presynaptic role for muscarinic autoreceptors in decreasing ACh release from olivocochlear terminals during high-level acoustic stimulation and suggest that muscarinic antagonists could enhance the resistance of the inner ear to noise-induced hearing loss.

Hearing and vestibular deficits in the Coch null mouse model: Comparison to the Coch mouse and to DFNA9 hearing and balance disorder

“…Lack of detection of any gross morphological changes in the Coch −/− mouse is a similar finding to that of the Coch G88E/G88E mouse model (Robertson et al, 2008), and similar to other examples of mutant mouse models with elevated ABR thresholds that do not show detectable histological abnormalities (Maison et al, 2006; Maison et al, 2010) . Our studies suggest that structural anomalies may not be detectable at a visible level, despite presence of overt symptoms, suggesting that pathology may be due to events occurring on a molecular level.…”

Dopaminergic Signaling in the Cochlea: Receptor Expression Patterns and Deletion Phenotypes

“…In immature ears (postnatal day 11 to 13), we dissected out the apical or middle cochlear turn and used pulled borosilicate glass tubing to aspirate individual IHCs, OHCs or spiral ganglion cells under direct visual control (see (Maison et al, 2010)). Between 6–20 cells were collected for each cell-type pool.…”

Physiological Activation of Cholinergic Inputs Controls Associative Synaptic Plasticity via Modulation of Endocannabinoid Signaling

“…Recent studies in mice lacking M1, M3, or M5 mAChRs displayed normal auditory brainstem responses (Maison et al, 2010). However, these studies assess baseline auditory brainstem response and based on our results, M1 and M3 mAChRs are expected to shape auditory response during learning or during adaptive processing (Tzounopoulos and Kraus, 2009).…”