CGRP's effect on hearing and balance in a mouse model of migraine

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Migraine is a severe and chronic neurological disorder that affects ~18% of people worldwide, majority female (3:1). Migraine is characterized by recurrent attacks of debilitating headaches and nausea, with heightened sensory sensitivities, such as light (photophobia) and sound (phonophobia). Recently it has become recognized that ~42% of migraine patients also suffer from balance problems and dizziness, termed vestibular migraine (VM). VM is a major cause of vertigo in dizziness clinics, and is estimated to affect 1% of the overall population. Clinically, triptans (serotonin 5-HT 1B/1D receptor agonists) can reduce photophobia and headaches in migraine, but often do not relieve other VM symptoms. Thus, there is an urgent need for validated preclinical models for VM. The neuropeptide calcitonin gene-related peptide (CGRP) is recognized as a key player in migraine based on the efficacy of CGRP blockers in clinical trials against headache, and injection of CGRP triggers migraine. We have developed CGRP-sensitized transgenic mouse models for migraine that have heightened responses to light (photophobia) when CGRP is delivered either centrally or systemically. We have shown that CGRP blockers can block CGRP-induced photosensitivity in these mice, yet CGRP blockers delivered systemically cannot effectively penetrate the CNS, and these blockers are not effective against centrally-induced photophobia, suggesting that photosensitivity in migraine involves both systemic and central components. CGRP is also widely distributed throughout the vestibular CNS, and CGRP-containing efferent fibers project to all inner ear endorgans. CGRP is also signaling in the vestibular and auditory systems, as we discovered in a different mouse model, that the loss of CGRP reduces the vestibulo-ocular reflex (VOR) gain, reduces otolith- evoked dynamics reduces, reduces sound-evoked activity in the cochlear nerve, and impairs rotarod (balance) performance. Yet, it is not yet known if CGRP is acting centrally or peripherally in VM; which would influence treatment routes and efficacy. We propose to measure mouse homologues of clinical VM symptoms namely; phonophobia, imbalance, nausea, and motion-sickness susceptibility; and will investigate these measures in three mouse lines: i) wildtype (WT) littermate controls and CGRP-sensitized mouse models with ii) neuronally- sensitized CGRP receptors (nestinRAMP1) or iii) globally-sensitized CGRP receptors (global RAMP1). Our hypothesis is that elevated CGRP-sensitivity will contribute to increased sensitivities found in VM; and that these VM symptoms will be ameliorated by CGRP blockers. Information gained from these studies will provide a direct assessment of whether CGRP-sensitized mouse models that have been shown to mirror the photophobia of migraine, can also mirror deficits observed in VM. Such a preclinical model of VM could be used for future translational studies to develop and test new therapeutics. !