Rescue of peripheral vestibular function in Usher syndrome mice using a splice-switching antisense oligonucleotide.

Usher syndrome type 1C (USH1C/harmonin) is associated with profound retinal, auditory and vestibular dysfunction. We have previously reported on an antisense oligonucleotide (ASO-29) that dramatically improves auditory function and balance behavior in mice homozygous for the harmonin mutation Ush1c c.216G > A following a single systemic administration. The findings were suggestive of improved vestibular function; however, no direct vestibular assessment was made. Here, we measured vestibular sensory evoked potentials (VsEPs) to directly assess vestibular function in Usher mice. We report that VsEPs are absent or abnormal in Usher mice, indicating profound loss of vestibular function. Strikingly, Usher mice receiving ASO-29 treatment have normal or elevated vestibular response thresholds when treated during a critical period between postnatal day 1 and 5, respectively. In contrast, treatment of mice with ASO-29 treatment at P15 was minimally effective at rescuing vestibular function. Interestingly, ASO-29 treatment at P1, P5 or P15 resulted in sufficient vestibular recovery to support normal balance behaviors, suggesting a therapeutic benefit to balance with ASO-29 treatment at P15 despite the profound vestibular functional deficits that persist with treatment at this later time. These findings provide the first direct evidence of an effective treatment of peripheral vestibular function in a mouse model of USH1C and reveal the potential for using antisense technology to treat vestibular dysfunction.

Effect of M-current modulation on mammalian vestibular responses to transient head motion.

The precise role and mechanisms underlying efferent modulation of peripheral vestibular afferent function are not well understood in mammals. Clarifying the details of efferent action may lead to new strategies for clinical management of debilitating disturbances in vestibular and balance function. Recent evidence in turtle indicates that efferent modulation of M-currents is likely one mechanism for modifying afferent discharge. M-currents depend in part on KCNQ potassium conductances (Kv7), which can be adjusted through efferent activation of M1, M3, and/or M5 muscarinic acetylcholine receptors (mAChRs). How KCNQ channels and altered M-currents affect vestibular afferent function in vivo is unclear, and whether such a mechanism operates in mammals is unknown. In this study we used the KCNQ antagonist XE991 and the KCNQ activator retigabine in anesthetized mice to evaluate the effects of M-current modulation on peripheral vestibular responses to transient head motion. At low doses of XE991, responses were modestly enhanced, becoming larger in amplitude and shorter in latency. Higher doses of XE991 produced transient response enhancement, followed by steady-state suppression where latencies and thresholds increased and amplitudes decreased. Retigabine produced opposite effects. Auditory function was also impacted, based on results of companion auditory brain stem response testing. We propose that closure of KCNQ channels transforms vestibular afferent behavior by suppressing responses to transient high-frequency stimuli while simultaneously enhancing responses to sustained low-frequency stimulation. Our results clearly demonstrate that KCNQ channels are critical for normal mammalian vestibular function and suggest that efferent action may utilize these mechanisms to modulate the dynamic characteristics and gain of vestibular afferent responses.NEW & NOTEWORTHY The role of calyceal KCNQ channels and associated M-current in normal mammalian vestibular function is unknown. Our results show that calyceal KCNQ channels are critical for normal vestibular function in the intact mammal. The findings provide evidence that efferent modulation of M-currents may act normally to differentially adjust the sensitivity of vestibular neurons to transient and tonic stimulation and that such mechanisms may be targeted to achieve effective clinical management of vestibular disorders.

A study of whirlin isoforms in the mouse vestibular system suggests potential vestibular dysfunction in DFNB31-deficient patients.

The DFNB31 gene plays an indispensable role in the cochlea and retina. Mutations in this gene disrupt its various isoforms and lead to non-syndromic deafness, blindness and deaf-blindness. However, the known expression of Dfnb31, the mouse ortholog of DFNB31, in vestibular organs and the potential vestibular-deficient phenotype observed in one Dfnb31 mutant mouse (Dfnb31(wi/wi)) suggest that DFNB31 may also be important for vestibular function. In this study, we find that full-length (FL-) and C-terminal (C-) whirlin isoforms are expressed in the vestibular organs, where their stereociliary localizations are similar to those of developing cochlear inner hair cells. No whirlin is detected in Dfnb31(wi/wi) vestibular organs, while only C-whirlin is expressed in Dfnb31(neo/neo) vestibular organs. Both FL- and C-whirlin isoforms are required for normal vestibular stereociliary growth, although they may play slightly different roles in the central and peripheral zones of the crista ampullaris. Vestibular sensory-evoked potentials demonstrate severe to profound vestibular deficits in Dfnb31(neo/neo) and Dfnb31(wi/wi) mice. Swimming and rotarod tests demonstrate that the two Dfnb31 mutants have balance problems, with Dfnb31(wi/wi) mice being more affected than Dfnb31(neo/neo) mice. Because Dfnb31(wi/wi) and Dfnb31(neo/neo) mice faithfully recapitulate hearing and vision symptoms in patients, our findings of vestibular dysfunction in these Dfnb31 mutants raise the question of whether DFNB31-deficient patients may acquire vestibular as well as hearing and vision loss.

Vestibular dysfunction, altered macular structure and trait localization in A/J inbred mice.

A/J mice develop progressive hearing loss that begins before 1 month of age and is attributed to cochlear hair cell degeneration. Screening tests indicated that this strain also develops early onset vestibular dysfunction and has otoconial deficits. The purpose of this study was to characterize the vestibular dysfunction and macular structural pathology over the lifespan of A/J mice. Vestibular function was measured using linear vestibular evoked potentials (VsEPs). Macular structural pathology was evaluated using light microscopy, scanning electron microscopy, transmission electron microscopy, confocal microscopy and Western blotting. Individually, vestibular functional deficits in mice ranged from mild to profound. On average, A/J mice had significantly reduced vestibular sensitivity (elevated VsEP response thresholds and smaller amplitudes), whereas VsEP onset latency was prolonged compared to age-matched controls (C57BL/6). A limited age-related vestibular functional loss was also present. Structural analysis identified marked age-independent otoconial abnormalities in concert with some stereociliary bundle defects. Macular epithelia were incompletely covered by otoconial membranes with significantly reduced opacity and often contained abnormally large or giant otoconia as well as normal-appearing otoconia. Elevated expression of key otoconins (i.e., otoconin 90, otolin and keratin sulfate proteoglycan) ruled out the possibility of reduced levels contributing to otoconial dysgenesis. The phenotype of A/J was partially replicated in a consomic mouse strain (C57BL/6J-Chr 17(A/J)/NaJ), thus indicating that Chr 17(A/J) contained a trait locus for a new gene variant responsible to some extent for the A/J vestibular phenotype. Quantitative trait locus analysis identified additional epistatic influences associated with chromosomes 1, 4, 9 and X. Results indicate that the A/J phenotype represents a complex trait, and the A/J mouse strain presents a new model for the study of mechanisms underlying otoconial formation and maintenance.

Pathophysiological processes underlying hidden hearing loss revealed in Kcnt1/2 double knockout mice.

Presbycusis is a prevalent condition in older adults characterized by the progressive loss of hearing due to age-related changes in the cochlea, the auditory portion of the inner ear. Many adults also struggle with understanding speech in noise despite having normal auditory thresholds, a condition termed "hidden" hearing loss because it evades standard audiological assessments. Examination of animal models and postmortem human tissue suggests that hidden hearing loss is also associated with age-related changes in the cochlea and may, therefore, precede overt age-related hearing loss. Nevertheless, the pathological mechanisms underlying hidden hearing loss are not understood, which hinders the development of diagnostic biomarkers and effective treatments for age-related hearing loss. To fill these gaps in knowledge, we leveraged a combination of tools, including transcriptomic profiling and morphological and functional assessments, to identify these processes and examine the transition from hidden to overt hearing loss. As a novel approach, we took advantage of a recently characterized model of hidden hearing loss: Kcnt1/2 double knockout mice. Using this model, we find that even before observable morphological pathology, hidden hearing loss is associated with significant alteration in several processes, notably proteostasis, in the cochlear sensorineural structures, and increased susceptibility to overt hearing loss in response to noise exposure and aging. Our findings provide the first insight into the pathophysiology associated with the earliest and, therefore, most treatable stages of hearing loss and provide critical insight directing future investigation of pharmaceutical strategies to slow and possibly prevent overt age-related hearing loss.

Real-ear output measures of ear level fluency devices.

OBJECTIVE: The purpose of this study was to measure real-ear aided and saturated responses of SpeechEasy™ devices and compare responses while devices delivered altered auditory feedback (AAF) and non-altered feedback (NAF). DESIGN: A repeated measures quasi-experimental design was employed. STUDY SAMPLE: Ten people fitted with completely-in-the-canal or open fit behind-the-ear devices participated. Probe microphone measures were obtained with speech, and 17 chirp stimuli presented at 75 dB and 85 dB SPL, respectively. Measurements were compared with devices delivering AAF (i.e. delayed and frequency shifted) versus NAF. RESULTS: Maximum outputs were approximately 100-105 dB SPL in the 2000-4000 Hz range. Statistically significant differences in device SPL output as a function of device setting (AAF vs. NAF) were found for seven chirp stimuli (p <.05) when levels were sampled at points that were not temporally aligned with the output chirps but not for speech stimulus (p = .17). Device output varied across individuals and with open fit devices dominated by ear canal resonance effects. CONCLUSIONS: Real-ear aided responses were equivalent with speech input when devices delivered AAF and NAF. Real-ear saturated responses were not, however, comparable between AAF and NAF settings and may be underestimated if AAF delay is not accounted for.

Effects of Several Therapeutic Agents on Mammalian Vestibular Function: Meclizine, Diazepam, and JNJ7777120.

Management of vestibular dysfunction may include treatment with medications that are thought to act to suppress vestibular function and reduce or eliminate abnormal sensitivity to head motions. The extent to which vestibular medications act centrally or peripherally is still debated. In this study, two commonly prescribed medications, meclizine and diazepam, and a candidate for future clinical use, JNJ7777120, were evaluated for their effects on short latency compound action potentials generated by the peripheral vestibular system and corresponding central neural relays (i.e., vestibular sensory-evoked potentials, VsEPs). The effects of the selected drugs developed slowly over the course of two hours in the mouse. Findings indicate that meclizine (600 mg/kg) and diazepam (> 60 mg/kg) can act on peripheral elements of the vestibular maculae whereas diazepam also acts most effectively on central gravity receptor circuits to exert its suppressive effects. The novel pharmacological agent JNJ7777120 (160 mg/kg) acts in the vestibular periphery to enhance macular responses to transient stimuli (VsEPs) while, hypothetically, suppressing macular responses to sustained or slowly changing stimuli.

Stimulus duration and vestibular sensory evoked potentials (VsEPs).

Recording the linear vestibular sensory evoked potential (VsEP) relies on moving the head in a prescribed manner to synchronously activate neurons of the gravity receptor organs. One problematic issue in accomplishing this is the potential coactivation of cochlear neurons. Although the major stimulus parameters required to elicit the vestibular response have been characterized, some of the determinants of auditory coactivation have not been clearly addressed. In the present study, we show that the duration of the linear cranial jerk stimulus plays a critical role in avoiding coactivation of auditory responses during VsEP recordings. Acoustic masking procedures are essential when recording the VsEP, particularly when using stimulus durations of less than 1 ms.

Functional cooperation between two otoconial proteins Oc90 and Nox3.

BACKGROUND: Otoconia-related vertigo and balance deficits are common in humans, but the molecular etiology is unknown at present. OBJECTIVE: In order to study mechanisms of otoconia formation and maintenance, we have investigated whether otoconin-90 (Oc90), the predominant otoconial constituent protein, and the NADPH oxidase Nox3, an essential regulatory protein for otoconia formation, are functionally interlinked. METHODS: We performed balance behavioral, electrophysiological, morphological and molecular cellular analyses. RESULTS: Double heterozygous mutant mice for Oc90 and Nox3 show severe imbalance, albeit less profound than double null mutants. In contrast, single heterozygous mutant mice have normal balance. Double heterozygous mice have otoconia defects and double null mice have no otoconia. In addition, some hair bundles in the latter mice go through accelerated degeneration. In vitro calcification analysis in cells stably expressing these proteins singly and doubly shows much more intense calcification in the double transfectants. CONCLUSIONS: Oc90 and Nox3 augment each other's function, which is not only critical for otoconia formation but also for hair bundle maintenance.

Antisense Oligonucleotides for the Treatment of Inner Ear Dysfunction.

Antisense oligonucleotides (ASOs) have shown potential as therapeutic molecules for the treatment of inner ear dysfunction. The peripheral sensory organs responsible for both hearing and equilibrium are housed within the inner ear. Hearing loss and vestibular balance problems affect a large portion of the population and limited treatment options exist. Targeting ASOs to the inner ear as a therapeutic strategy has unique pharmacokinetic and drug delivery opportunities and challenges. Here, we review ASO technology, delivery, disease targets, and other key considerations for development of this therapeutic approach.

Spontaneous mutations of the Zpld1 gene in mice cause semicircular canal dysfunction but do not impair gravity receptor or hearing functions.

The cupula is a gelatinous membrane overlying the crista ampullaris of the semicircular canal, important for sensing rotation of the head and critical for normal balance. Recently the zona pellucida like domain containing 1 protein (ZPLD1, also known as cupulin) was identified in the cupula of fish. Here, we describe two new spontaneous mutations in the mouse Zpld1 gene, which were discovered by the circling behavior of mutant mice, an indicator of balance dysfunction. The Zpld1 mutant mice exhibited normal hearing function as assessed by auditory brainstem response (ABR) measurements, and their otolithic organs appeared normal. In the inner ear, Zpld1 mRNA expression was detected only in the hair cells and supporting cells of the crista ampullaris. Normal vestibular sensory evoked potential (VsEP) responses and abnormal vestibulo-ocular reflex (VOR) responses demonstrated that the vestibular dysfunction of the Zpld1 mutant mice is caused by loss of sensory input for rotary head movements (detected by cristae ampullaris) and not by loss of input for linear head translations (detected by maculae of the utricle and saccule). Taken together, these results are consistent with ZPLD1 being an important functional component of the cupula, but not tectorial or otoconial membranes.

Sodium-activated potassium channels shape peripheral auditory function and activity of the primary auditory neurons in mice.

Potassium (K+) channels shape the response properties of neurons. Although enormous progress has been made to characterize K+ channels in the primary auditory neurons, the molecular identities of many of these channels and their contributions to hearing in vivo remain unknown. Using a combination of RNA sequencing and single molecule fluorescent in situ hybridization, we localized expression of transcripts encoding the sodium-activated potassium channels KNa1.1 (SLO2.2/Slack) and KNa1.2 (SLO2.1/Slick) to the primary auditory neurons (spiral ganglion neurons, SGNs). To examine the contribution of these channels to function of the SGNs in vivo, we measured auditory brainstem responses in KNa1.1/1.2 double knockout (DKO) mice. Although auditory brainstem response (wave I) thresholds were not altered, the amplitudes of suprathreshold responses were reduced in DKO mice. This reduction in amplitude occurred despite normal numbers and molecular architecture of the SGNs and their synapses with the inner hair cells. Patch clamp electrophysiology of SGNs isolated from DKO mice displayed altered membrane properties, including reduced action potential thresholds and amplitudes. These findings show that KNa1 channel activity is essential for normal cochlear function and suggest that early forms of hearing loss may result from physiological changes in the activity of the primary auditory neurons.

Effects of Ketamine Compared with Urethane Anesthesia on Vestibular Sensory Evoked Potentials and Systemic Physiology in Mice.

The injectable anesthetic mixture ketamine-xylazine is commonly used for electrophysiologic experiments in laboratory animals, especially rodents. General anesthesia can induce significant changes in systemic physiology, including those that compromise neural function, thus introducing research confounds. The extent of such concerns varies by agent. Here in mice, we compared the effects of ketamine-xylazine and urethane-xylazine anesthesia on systemic physiologic parameters and the vestibular sensory evoked potential (VsEP), a tool used commonly to assess peripheral vestibular function. Urethane-xylazine anesthesia provided longer anesthesia, prolonged survival times, and less compromised respiratory and cardiovascular function, compared with ketamine-xylazine. In the absence of countermeasures, mice anesthetized with either ketamine-xylazine or urethane-xylazine showed evidence of hypoxemia and fluctuations in brain temperature, heart rate, respiration rate, and VsEP response latency. The levels of hypoxemia had no effect on VsEP response parameters over the period of study (2 to 5 h). Hypoxemia was effectively countered with O2 supplementation, which stabilized respiratory rates and improved mean survival times by 160% in mice anesthetized with ketamine-xylazine. Monitoring and controlling brain temperature reduced variation in VsEP latency. VsEP thresholds, latencies, and amplitudes did not differ between mice under ketamine-xylazine compared with urethane-xylazine when the brain temperature was held at the same set point. These findings demonstrate that urethane-xylazine provides improved systemic physiologic conditions during anesthesia in mice and may be substituted for ketamine-xylazine in studies using the VsEP to evaluate peripheral vestibular function. Such advantages may prove useful to research in other neuroscience areas and might reduce the number of animals used to achieve adequate sample sizes.

Acute blockade of inner ear marginal and dark cell K+ secretion: Effects on gravity receptor function.

Specific pharmacological blockade of KCNQ (Kv7) channels with XE991 rapidly (within 20 min) and profoundly alters inner ear gravity receptor responses to head motion (Lee et al., 2017). We hypothesized that these effects were attributable to the suppression of K+ secretion following blockade of KCNQ1-KCNE1 channels in vestibular dark cells and marginal cells. To test this hypothesis, K+ secretion was independently inhibited by blocking the Na+-K+-2Cl- cotransporter (NKCC1, Slc12a2) rather than KCNQ1-KCNE1 channels. Acute blockade of NKCC1 with ethacrynic acid (40 mg/kg) eliminated auditory responses (ABRs) within approximately 70 min of injection, but had no effect on vestibular gravity receptor function (VsEPs) over a period of 2 h in the same animals. These findings show that, vestibular gravity receptors are highly resistant to acute disruption of endolymph secretion unlike the auditory system. Based on this we argue that acute suppression of K+ secretion alone does not likely account for the rapid profound effects of XE991 on gravity receptors. Instead the effects of XE991 likely require additional action at KCNQ channels located within the sensory epithelium itself.

Neuropharmacological Targets for Drug Action in Vestibular Sensory Pathways.

The use of pharmacological agents is often the preferred approach to the management of vestibular dysfunction. In the vestibular sensory pathways, the sensory neuroepithelia are thought to be influenced by a diverse number of neuroactive substances that may act to enhance or inhibit the effect of the primary neurotransmitters [i.e., glutamate (Glu) and acetylcholine (ACh)] or alter their patterns of release. This review summarizes various efforts to identify drug targets including neurotransmitter and neuromodulator receptors in the vestibular sensory pathways. Identifying these receptor targets provides a strategic basis to use specific pharmacological tools to modify receptor function in the treatment and management of debilitating balance disorders. A review of the literature reveals that most investigations of the neuropharmacology of peripheral vestibular function have been performed using in vitro or ex vivo animal preparations rather than studying drug action on the normal intact vestibular system in situ. Such noninvasive approaches could aid the development of more accurate and effective intervention strategies for the treatment of dizziness and vertigo. The current review explores the major neuropharmacological targets for drug action in the vestibular system.

Nicotinic acetylcholine receptors regulate vestibular afferent gain and activation timing.

Little is known about the function of the cholinergic efferents innervating peripheral vestibular hair cells. We measured vestibular sensory evoked potentials (VsEPs) in α9 knockout (KO) mice, α10 KO mice, α7 KO mice, α9/10 and α7/9 double KO mice, and wild-type (WT) controls. We also studied the morphology and ultrastructure of efferent terminals on vestibular hair cells in α9, α10, and α9/10 KOs. Both type I and type ll vestibular hair cells express the α9 and α10 subunits. The efferent boutons on vestibular cells in α9, α10, and α9/10 KOs appeared normal, but a quantitative analysis was not performed. Mean VsEP thresholds were significantly elevated in α9 and α9/10 KO animals. Some α9 and α9/10 KO animals, however, had normal or near-normal thresholds, whereas others were greatly affected. Despite individual variability in threshold responses, latencies were consistently shortened. The double α7/9 KO resulted in decreased variance by normalizing waveforms and latencies. The phenotypes of the α7 and α10 single KOs were identical. Both α7 and α10 KO mice evidenced normal thresholds, decreased activation latencies, and larger amplitudes compared with WT mice. The data suggest a complex interaction of nicotinic acetylcholine receptors (nAChRs) in regulating vestibular afferent gain and activation timing. Although the α9/10 heteromeric nAChR is an important component of vestibular efferent activity, other peripheral or central nAChRs involving the α7 subunit or α10 subunit and α9 homomeric receptors are also important. J. Comp. Neurol. 525:1216-1233, 2017. © 2016 Wiley Periodicals, Inc.

A comparison of vestibular and auditory phenotypes in inbred mouse strains.

The purposes of this research were to quantify gravity receptor function in inbred mouse strains and compare vestibular and auditory function for strain- and age-matched animals. Vestibular evoked potentials (VsEPs) were collected for 19 inbred strains at ages from 35 to 389 days old. On average, C57BL/6J (35 to 190 days), BALB/cByJ, C3H/HeSnJ, CBA/J, and young LP/J mice had VsEP thresholds comparable to normal. Elevated VsEP thresholds were found for elderly C57BL/6J, NOD.NONH2(kb), BUB/BnJ, A/J, DBA/2J, NOD/LtJ, A/WySnJ, MRL/MpJ, A/HeJ, CAST/Ei, SJL/J, elderly LP/J, and CE/J. These results suggest that otolithic function varies among inbred strains and several strains displayed gravity receptor deficits by 90 days old. Auditory brainstem response (ABR) thresholds were compared to VsEP thresholds for 14 age-matched strains. C57BL/6J mice (up to 190 days) showed normal VsEPs with normal to mildly elevated ABR thresholds. Four strains (BUB/BnJ, NOD/LtJ, A/J, elderly LP/J) had significant hearing loss and elevated VsEP thresholds. Four strains (DBA/2J, A/WySnJ, NOD.NONH2(kb), A/HeJ) had elevated VsEP thresholds (including absent VsEPs) with mild to moderate elevations in ABR thresholds. Three strains (MRL/MpJ, Ce/J, SJL/J) had significant vestibular loss with no concomitant hearing loss. These results suggest that functional change in one sensory system does not obligate change in the other. We hypothesize that genes responsible for early onset hearing loss may affect otolithic function, yet the time course of functional change may vary. In addition, some genetic mutations may produce primarily gravity receptor deficits. Potential genes responsible for selective gravity receptor impairment demonstrated herein remain to be identified.

Afferent synapses are present in utricular hair cells from otoconia-deficient mice.

The head tilt mouse (het/het, abbr. het) is a naturally occurring mutant whose salient phenotypic traits include the complete absence of otoconia in both the utricle and saccule. Cursory histologic evaluation has indicated that the neuroepithelia exhibit a normal appearance. Though evidence exists indicating that utricular function is severely if not completely compromised in these animals, it is not yet known whether afferent synapses exist within utricular hair cells of otoconia-deficient mutants. The absence of synapses would be suggestive of a trophic relationship between stimulus-evoked hair cell activation and the afferent synapse. To address this question, we have conducted an ultrastructural survey of utricular sensory epithelia from confirmed het mice. The specific objective was to determine whether utricular hair cells made synaptic contact with afferent neurons. We found that both type I and II hair cells from utricles of het mice exhibited afferent synapses that were found at numerous sites distributed throughout the utricle. These results indicate that afferent synapses within vestibular hair cells do not critically depend upon stimulus-evoked activity.

Differential effects of Cdh23(753A) on auditory and vestibular functional aging in C57BL/6J mice.

The C57BL/6J (B6) mouse strain carries a cadherin 23 mutation (Cdh23(753A), also known as Ahl), which affects inner ear structures and results in age-related hearing loss. The B6.CAST strain harbors the wild type Cdh23 gene, and hence, the influence of Ahl is absent. The purpose of the present study was to characterize the effect of age and gender on gravity receptor function in B6 and B6.CAST strains and to compare functional aging between auditory and vestibular modalities. Auditory sensitivity declined at significantly faster rates than gravity receptor sensitivity for both strains. Indeed, vestibular functional aging was minimal for both strains. The comparatively smaller loss of macular versus cochlear sensitivity in both the B6 and B6.CAST strains suggests that the contribution of Ahl to the aging of the vestibular system is minimal, and thus very different than its influence on aging of the auditory system. Alternatively, there exist unidentified genes or gene modifiers that serve to slow the degeneration of gravity receptor structures and maintain gravity receptor sensitivity into advanced age.

A quantitative survey of gravity receptor function in mutant mouse strains.

The purpose of this research was to identify vestibular deficits in mice using linear vestibular evoked potentials (VsEPs). VsEP thresholds, peak latencies, and peak amplitudes from 24 strains with known genetic mutations and 6 inbred background strains were analyzed and descriptive statistics generated for each strain. Response parameters from mutant homozygotes were compared with heterozygote and/or background controls and all strain averages were contrasted to normative ranges. Homozygotes of the following recessive mutations had absent VsEPs at the ages tested: Espn(je), Atp2b2dfw-2J, Spnb4qv-lnd2J, Spnb4qv-3J, Myo7ash1, Tmie(sr), Myo6sv, jc, Pcdh15av-J, Pcdh15av-2J, Pcdh15av-3J, Cdh23v-2J, Sans(js), hr, Kcne1pkr and Pou3f4del. These results suggest profound gravity receptor deficits for these homozygotes, which is consistent with the structural deficits that have been documented for many of these strains. Homozygotes of Catna2cdf, Grid2ho4J, Wnt1sw, qk, and Mbpshi strains and heterozygotes of Grid2lc had measurable VsEPs but one or more response parameters differed from the respective control group (heterozygote or background strain) or were outside normal ranges. For example, qk and Mbpshi homozygotes showed significantly prolonged latencies consistent with the abnormal myelin that has been described for these strains. Prolonged latencies may suggest deficits in neural conduction; elevated thresholds suggest reduced sensitivity, and reduced amplitudes may be suggestive for reduced neural synchrony. One mutation, Otx1jv, had all VsEP response parameters within normal limits--an expected finding because the abnormality in Otxljv is presumably restricted to the lateral semicircular canal. Interestingly, some heterozygote groups also showed abnormalities in one or more VsEP response parameters, suggesting that vestibular dysfunction, although less severe, may be present in some heterozygous animals.