Maturation of suprathreshold auditory nerve activity involves cochlear CGRP–receptor complex formation

Abstract

In adult animals, the neuropeptide calcitonin gene‐related peptide (CGRP) is contained in cochlear efferent fibers projecting out to the cochlea, and contributes to increased suprathreshold sound‐evoked activity in the adult auditory nerve. Similarly, CGRP applied to the lateral‐line organ (hair cell organ) increases afferent nerve activity in adult frogs (post‐metamorphic day 30), yet this increase is developmentally delayed from post‐metamorphic day 4–30. In this study, we discovered that there was also a developmental delay in increased suprathreshold sound‐evoked activity auditory nerve between juvenile and adult mice similar to what had been observed previously in frog. Moreover, juvenile mice with a targeted deletion of the α CGRP gene [CGRP null (−/−)] did not show a similar developmental increase in nerve activity, suggesting CGRP signaling is involved. This developmental delay is not due to a delay in CGRP expression, but instead is due to a delay in receptor formation. We observed that the increase in sound‐evoked nerve activity is correlated with increased formation of cochlear CGRP receptors, which require three complexed proteins (CLR, RAMP1, RCP) to be functional. CGRP receptor formation in the cochlea was incomplete at 1 month of age (juvenile), but complete by 3 months (adult), which corresponded to the onset of suprathreshold enhancement of sound‐evoked activity in wild‐type animals. Taken together, these data support a model for cochlear function that is enhanced by maturation of CGRP receptor complexes.

Generation and Characterization of α9 and α10 Nicotinic Acetylcholine Receptor Subunit Knockout Mice on a C57BL/6J Background

“…The C57BL/6J strain carries an age-related hearing loss locus that affects hearing. Additionally, 1–3 month old mice show a developmental delay in suprathreshold sound-evoked activity of the auditory nerve (Dickerson et al, 2016 ). In order to show age was not related to the results obtained here, the animals were tested at a young age and efferent mediated adaptation scores were plotted as a function of age.…”

Reflex Modification Audiometry Reveals Dual Roles for Olivocochlear Neurotransmission

“…These mice were generated and maintained on a FVB/NJ background and bred as heterozygotes for transgenic mice expressing the Ld'T mutation and wildtype littermate controls, with N = 12 (6M/6F) mice in each group. And finally, αCGRP (–/–) mice (on a 129SvEv background), originally generated by Dr. Ron Emeson's laboratory (Lu et al, 1999 ) with an active breeding colony at the University of Rochester (Dickerson et al, 2016 ), were bred as heterozygotes to generate αCGRP (–/–) null and (+/+) wildtype littermates. Again N = 12 (6M/6F) αCGRP (–/–) and (+/+) mice were tested.…”

“…We then employ these measures to assess behavioral responses in quiet and background noise in mice (with their littermate controls) either lacking the MOC receptor subunit α9 nicotinic acetylcholine receptor [α9 nAChR (–/–)] or expressing an overactive receptor [Ld'T mutation in α9 nAChR KI], or lacking a LOC efferent neuropeptide, alpha calcitonin gene-related peptide [αCGRP (–/–)] (Elgoyhen et al, 1994 ; Lu et al, 1999 ; Maison et al, 2003a ; Taranda et al, 2009 ). Because CGRP receptor formation matures from juvenile to adult ages, which is correlated with the increase observed in wave 1 amplitude of the auditory brainstem response (ABR), we also asked if a similar maturation in PPI responses can be observed between juvenile and adult (+/+) control and adult CGRP (–/–) animals (Dickerson et al, 2016 ).…”

“…Loss of either the MOC or LOC system after cochlear development does not affect auditory thresholds, yet both systems are activated by sound. Sound suppresses MOC responses (as assessed by otoacoustic emissions and cochlear action potentials and nerve activity) and CGRP transmission through the LOC system has been shown to enhance suprathreshold cochlear nerve activity suggesting that both systems may work in tandem to enhance behavioral responses to sound (Maison et al, 2002 , 2003a ; Guinan et al, 2005 ; Guinan, 2006 , 2010 , 2013 , 2014 ; Le Prell et al, 2014a , b ; Dickerson et al, 2016 ).…”

Recommendations on the Use of Anti‐CGRP Monoclonal Antibodies in Children and Adolescents

“…CGRP and its receptors are expressed in significant concentrations during postnatal animal brain development and are likely involved in central nervous system maturation . CGRP may also play a role in nervous system recovery after injury .…”