Loss of α-Calcitonin Gene-Related Peptide (αCGRP) Reduces Otolith Activation Timing Dynamics and Impairs Balance.

Sherri M Jones,Joseph C Holt,Samantha A Dow,Anne E Luebke,Sarath Vijayakumar,Paivi M Jordan

doi:10.3389/fnmol.2018.00289

Abstract

Calcitonin gene-related peptide (CGRP) is a neuroactive peptide that is thought to play a role at efferent synapses in hair cell organs including the cochlea, lateral line, and semicircular canal. The deletion of CGRP in transgenic mice is associated with a significant reduction in suprathreshold cochlear nerve activity and vestibulo–ocular reflex (VOR) gain efficacy when compared to littermate controls. Here we asked whether the loss of CGRP also influences otolithic end organ function and contributes to balance impairments. Immunostaining for CGRP was absent in the otolithic end organs of αCGRP null (-/-) mice while choline acetyltransferase (ChAT) immunolabeling appeared unchanged suggesting the overall gross development of efferent innervation in otolithic organs was unaltered. Otolithic function was assessed by quantifying the thresholds, suprathreshold amplitudes, and latencies of vestibular sensory-evoked potentials (VsEPs) while general balance function was assessed using a modified rotarod assay. The loss of αCGRP in null (-/-) mice was associated with: (1) shorter VsEP latencies without a concomitant change in amplitude or thresholds, and (2) deficits in the rotarod balance assay. Our findings show that CGRP loss results in faster otolith afferent activation timing, suggesting that the CGRP component of the efferent vestibular system (EVS) also plays a role in otolithic organ dynamics, which when coupled with reduced VOR gain efficacy, impairs balance.

Highlights

Calcitonin gene-related peptide (CGRP) is a 37 amino-acid neuroactive peptide commonly found in efferent neurons innervating hair cell organs including the cochlea, lateral line, semicircular canals, and otolithic end organs (Adams et al, 1987; Wackym et al, 1993; Maison et al, 2003a,b; Dickerson et al, 2016)
We show that mice with a targeted deletion of the αCGRP gene display a decrease in otolith activation timing and balance impairments
The loss of αCGRP in (−/−) null mice was linked to a significant shortening of the vestibular sensory-evoked potentials (VsEPs) latency without concomitant changes in thresholds or amplitudes

Summary

Introduction

Calcitonin gene-related peptide (CGRP) is a 37 amino-acid neuroactive peptide commonly found in efferent neurons innervating hair cell organs including the cochlea, lateral line, semicircular canals, and otolithic end organs (Adams et al, 1987; Wackym et al, 1993; Maison et al, 2003a,b; Dickerson et al, 2016). In mammals (Figures 1A,B), the efferent vestibular system (EVS) begins as hundreds of parent neurons in the dorsal brainstem, which project bilaterally and branch extensively to make numerous synapses on type II hair cells and afferent terminals including calyces surrounding type I hair cells 2006; Lysakowski and Goldberg, 2008) At these synapses, CGRP is commonly colocalized in presynaptic efferent varicosities with choline acetyltransferase (ChAT), the enzyme that catalyzes the synthesis of acetylcholine (ACh), the predominant EVS transmitter (Goldberg, 2000). Recent pharmacological evidence has demonstrated a role for alpha9-containing nicotinic ACh receptors (α9 nAChRs) on type II hair cells and alpha4beta2containing nAChRs and muscarinic AChRs on bouton and calyx-bearing afferents (Holt et al, 2015, 2017; Poppi et al, 2018)

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