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

Luebke, Anne E.; Holt, Joseph C.; Jordan, Paivi M.; Wong, Yi Shan; Caldwell, Jillian; Cullen, Kathleen E.

doi:10.1523/jneurosci.3336-13.2014

Cited by 54 publications

(58 citation statements)

References 25 publications

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“…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.…”

Section: Discussionsupporting

confidence: 92%

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

Hübner

Khan

Migliaccio

2015

Journal of Neurophysiology

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Hübner PP, Khan SI, Migliaccio AA. The mammalian efferent vestibular system plays a crucial role in the high-frequency response and short-term adaptation of the vestibuloocular reflex. J Neurophysiol 114: 3154 -3165, 2015. First published September 30, 2015 doi:10.1152/jn.00307.2015.-Although anatomically well described, the functional role of the mammalian efferent vestibular system (EVS) remains unclear. Unlike in fish and reptiles, the mammalian EVS does not seem to play a role in modulation of primary afferent activity in anticipation of active head movements. However, it could play a role in modulating long-term mechanisms requiring plasticity such as vestibular adaptation. We measured the efficacy of vestibuloocular reflex (VOR) adaptation in ␣9-knockout mice. These mice carry a missense mutation of the gene encoding the ␣9 nicotinic acetylcholine receptor (nAChR) subunit. The ␣9 nAChR subunit is expressed in the vestibular and auditory periphery, and its loss of function could compromise peripheral input from the predominantly cholinergic EVS. We measured the VOR gain (eye velocity/head velocity) in 26 ␣9-knockout mice and 27 cba129 control mice. Mice were randomly assigned to one of three groups: gain-increase adaptation (1.5ϫ), gain-decrease adaptation (0.5ϫ), or no adaptation (baseline, 1ϫ). After adaptation training (horizontal rotations at 0.5 Hz with peak velocity 20°/s), we measured the sinusoidal (0.2-10 Hz, 20 -100°/s) and transient (1,500 -6,000°/s 2 ) VOR in complete darkness. ␣9-Knockout mice had significantly lower baseline gains compared with control mice. This difference increased with stimulus frequency (ϳ5% Ͻ1 Hz to ϳ25% Ͼ1 Hz). Moreover, vestibular adaptation (difference in VOR gain of gain-increase and gain-decrease adaptation groups as % of gain increase) was significantly reduced in ␣9-knockout mice (17%) compared with control mice (53%), a reduction of ϳ70%. Our results show that the loss of ␣9 nAChRs moderately affects the VOR but severely affects VOR adaptation, suggesting that the EVS plays a crucial role in vestibular plasticity. efferent vestibular system; vestibular adaptation; vestibular plasticity; vestibuloocular reflex; ␣9-knockout mice DESPITE CONSIDERABLE EFFORT, the functional role of the mammalian efferent vestibular system (EVS) is poorly understood.

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Section: Discussionsupporting

confidence: 92%

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

Hübner

Khan

Migliaccio

2015

Journal of Neurophysiology

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“…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. ).…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Dickerson

Bussey-Gaborski

Holt

et al. 2016

Physiological Reports

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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.

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“…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).…”

Section: Antibody Characterizationmentioning

confidence: 99%

“…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).…”

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confidence: 99%

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

Jordan

Fettis

Holt

2015

J of Comparative Neurology

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In the vestibular periphery of nearly every vertebrate, cholinergic vestibular efferent neurons give rise to numerous presynaptic varicosities that target hair cells and afferent processes in the sensory neuroepithelium. Although pharmacological studies have described the postsynaptic actions of vestibular efferent stimulation in several species, characterization of efferent innervation patterns and the relative distribution of efferent varicosities among hair cells and afferents are also integral to understanding how efferent synapses operate. Vestibular efferent markers, however, have not been well characterized in the turtle, one of the animal models utilized by our laboratory. Here, we sought to identify reliable efferent neuronal markers in the vestibular periphery of turtle, to utilize these markers to understand how efferent synapses are organized, and to compare efferent neuronal labeling patterns in turtle with two other amniotes using some of the same markers. Efferent fibers and varicosities were visualized in the semicircular canal of Red-Eared Turtles (Trachemys scripta elegans), Zebra Finches (Taeniopygia guttata), and mice (Mus musculus) utilizing fluorescent immunohistochemistry with antibodies against choline acetyltransferase (ChAT). Vestibular hair cells and afferents were counterstained using antibodies to myosin VIIa and calretinin. In all species, ChAT labeled a population of small diameter fibers giving rise to numerous spherical varicosities abutting type II hair cells and afferent processes. That these ChAT-positive varicosities represent presynaptic release sites were demonstrated by colabeling with antibodies against the synaptic vesicle proteins synapsin I, SV2, or syntaxin and the neuropeptide calcitonin gene-related peptide (CGRP). Comparisons of efferent innervation patterns among the three species are discussed.

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

Cited by 54 publications

References 25 publications

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

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

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

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

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