Loss of  -Calcitonin Gene-Related Peptide ( CGRP) Reduces the Efficacy of the Vestibulo-ocular Reflex (VOR)

Abstract

The neuroactive peptide calcitonin-gene related peptide (CGRP) is known to act at efferent synapses and their targets in hair cell organs, including the cochlea and lateral line. CGRP is also expressed in vestibular efferent neurons as well as a number of central vestibular neurons. Although CGRP-null (؊/؊) mice demonstrate a significant reduction in cochlear nerve sound-evoked activity compared with wild-type mice, it is unknown whether and how the loss of CGRP influence vestibular system function. Vestibular function was assessed by quantifying the vestibulo-ocular reflex (VOR) in alert mice. The loss of CGRP in (؊/؊) mice was associated with a reduction of the VOR gain of Ϸ50% without a concomitant change in phase. Using immunohistochemistry, we confirmed that, although CGRP staining was absent in the vestibular end-organs of null (؊/؊) mice, cholinergic staining appeared normal, suggesting that the overall gross development of vestibular efferent innervation was unaltered. We further confirmed that the observed deficit in vestibular function of null (؊/؊) mice was not the result of nontargeted effects at the level of the extraocular motor neurons and/or their innervation of extraocular muscles. Analysis of the relationship between vestibular quick phase amplitude and peak velocity revealed that extraocular motor function was unchanged, and immunohistochemistry revealed no abnormalities in motor endplates. Together, our findings show that the neurotransmitter CGRP plays a key role in ensuring VOR efficacy.

The mammalian efferent vestibular system plays a crucial role in the high-frequency response and short-term adaptation of the vestibuloocular reflex

“…At stimulus frequencies Ͻ 1 Hz the difference was ϳ5% compared with ϳ25% at frequencies Ͼ 1 Hz. These findings are consistent with a recent study showing that calcitonin gene-related peptide (CGRP)-knockout mice (CGRP is expressed in vestibular efferents and important for EVS function) also had a reduction (ϳ50%) in baseline VOR gain (Luebke et al 2014). In contrast, the baseline VOR phase between ␣9-knockout and control mice was similar and did not change as a result of VOR adaptation training.…”

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

“…It is not known if this vestibular maturation also involves CGRP signaling maturation, yet CGRP signaling may also be involved, as we have recently determined that the loss of CGRP (−/−) in adult mice reduced the VOR gain by ~50% (Luebke et al. ).…”

“…In the vestibular system, there is an increase in the gain of the vestibular ocular reflex (VOR) from juvenile ages to adulthood (Faulstich et al 2004). It is not known if this vestibular maturation also involves CGRP signaling maturation, yet CGRP signaling may also be involved, as we have recently determined that the loss of CGRP (À/À) in adult mice reduced the VOR gain bỹ 50% (Luebke et al 2014). While CGRP receptor maturation was not specifically studied, changes in auditory sensitivity with juvenile-toadult maturation have been observed.…”

Efferent innervation of turtle semicircular canal cristae: Comparisons with bird and mouse

“…Antibody specificity was validated using immunoprecipitation (Rosenblatt and Dickerson, 1997). These antibodies label cholinergic efferent neurons in the guinea pig cochlea and mouse semicircular canal cristae (Cabanillas and Luebke, 2002;Luebke et al, 2014).…”

“…But specifying which ChAT-positive processes are synaptic would be further strengthened by additional labeling with distinct pre-and postsynaptic markers, as has been demonstrated at efferent (Zidanic, 2002;Osman et al, 2008;Wibowo et al, 2009;Roux et al, 2011) and afferent synapses in the auditory system (Khimich et al, 2005;Liberman et al, 2011). Several studies have investigated the distribution of efferent presynaptic or postsynaptic proteins in the peripheral vestibular system (Favre et al, 1986;Tanaka et al, 1989;Ishiyama et al, 1995;Dailey et al, 2000;Holstein et al, 2005;Luebke et al, 2005, Osman et al, 2008Castellano-Muñoz et al, 2010), but seldom in the context of colabeling with ChAT (Luebke et al, 2014). We addressed this gap using fluorescent immunohistochemistry with antibodies to ChAT and several well-characterized presynaptic markers to label cholinergic vestibular efferent fibers and varicosities in the crista of turtle (Trachemys scripta elegans), zebra finch (Taeniopygia guttata), and mouse (Mus musculus).…”