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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.

Migraine is a severe and chronic neurological disorder that affects ∼18% of people worldwide, the majority being female (3:1). It is characterized by recurrent, debilitating headaches and heightened sensory sensitivities. People with migraine may also experience a heightened motion sensitivity that leads to episodes of vertigo and imbalance, termed vestibular migraine (VM). Calcitonin Gene-Related Peptide (CGRP) is implicated in migraine and is believed to act on brain meninges, midbrain, or brainstem, and CGRP-based therapeutics have shown efficacy for migraine treatment. CGRP also signals at efferent synapses of the cochlea and vestibular endorgans, but it is unclear if exogenous CGRP can modulate inner ear function and cause heightened behavioral responses consistent with VM. In C57BL/6 mice, we tested if intraperitoneally (IP) delivered CGRP can modulate endorgan potentials to sound [via auditory brainstem responses (ABRs)] and jerk stimulus [via vestibular sensory evoked potentials (VsEPs)]. We also assessed behavioral measures of phonophobia [acoustic startle reflex (ASR)] and imbalance [postural sway-center of pressure (CoP)] after IP CGRP, and observed female mice exhibit heightened sensitivities to IP CGRP in all assays. Male mice showed similar auditory sensitivity and endorgan effects, but no postural sway changes. In conclusion, we show that systemically delivered CGRP modulates the nerve activity of the auditory and vestibular endorgans and elicits behavioral effects that are consistent with symptoms in a disorder like VM.Significance statementCalcitonin Gene-Related Peptide (CGRP) has been implicated in migraine, and CGRP-based therapeutics have shown efficacy in the treatment of migraine headaches. CGRP is also present in efferent synapses of the inner ear, but we questioned if increases in systemic CGRP can act directly on inner ear endorgans and modify corresponding behavioral responses. In this study, we determined systemic CGRP changes cochlear and vestibular endorgan potentials and produces behaviors suggestive of phonophobia and postural sway. Peripheral changes in auditory and vestibular compound action potentials following systemic CGRP administration suggest CGRP can act directly on the inner ear, which provides a basis for CGRP’s involvement in migraine with vertigo and as a therapeutic target.

Cochlear amplification of basilar membrane traveling waves is thought to occur between a tone’s characteristic frequency (CF) place and within one octave basal of the CF. Evidence for this view comes only from the cochlear base. Stimulus-frequency otoacoustic emissions (SFOAEs) provide a noninvasive alternative to direct measurements of cochlear motion that can be measured across a wide range of CF regions. Coherent reflection theory indicates that SFOAEs arise mostly from the peak region of the traveling wave, but several studies using far-basal suppressor tones claimed that SFOAE components originate many octaves basal of CF. We measured SFOAEs while perfusing guinea pig cochleas from apex to base with salicylate or KCl solutions that reduced outer-hair-cell function and SFOAE amplification. Solution effects on inner hair cells reduced auditory nerve compound action potentials (CAPs) and provided reference times for when solutions reached the SFOAE-frequency CF region. As solution flowed from apex to base, SFOAE reductions generally occurred later than CAP reductions and showed that the effects of cochlear amplification usually peaked ∼1/2 octave basal of the CF region. For tones ≥2 kHz, cochlear amplification typically extended ∼1.5 octaves basal of CF, and the data are consistent with coherent reflection theory. SFOAE amplification did not extend to the basal end of the cochlea, even though reticular lamina motion is amplified in this region, which indicates that reticular lamina motion is not directly coupled to basilar membrane traveling waves. Previous reports of SFOAE-frequency residuals produced by suppressor frequencies far above the SFOAE frequency are most likely due to additional sources created by the suppressor. For some tones

Endolymphatic hydrops is associated with low-frequency sensorineural hearing loss, with a large body of research dedicated to examining its putative causal role in low-frequency hearing loss. Investigations have been thwarted by the fact that hearing loss is measured in intact ears, but gold standard assessments of endolymphatic hydrops are made postmortem only; and that no objective low-frequency hearing measure has existed. Yet the association of endolymphatic hydrops with low-frequency hearing loss is so strong that it has been established as one of the important defining features for Ménière’s disease, rendering it critical to detect endolymphatic hydrops early, regardless of whether it serves a causal role or is the result of other disease mechanisms. We surgically induced endolymphatic hydrops in guinea pigs and employed our recently developed objective neural measure of low-frequency hearing, the Auditory Nerve Overlapped Waveform (ANOW). Hearing loss and endolymphatic hydrops were assessed at various time points after surgery. The ANOW detected low-frequency hearing loss as early as the first day after surgery, well before endolymphatic hydrops was found histologically. The ANOW detected low-frequency hearing loss with perfect sensitivity and specificity in all ears after endolymphatic hydrops developed, where there was a strong linear relationship between degree of endolymphatic hydrops and severity of low-frequency hearing loss. Further, histological data demonstrated that endolymphatic hydrops is seen first in the high-frequency cochlear base, though the ANOW demonstrated that dysfunction begins in the low-frequency apical cochlear half. The results lay the groundwork for future investigations of the causal role of endolymphatic hydrops in low-frequency hearing loss.

Little is known about the spatial origins of auditory nerve (AN) compound action potentials (CAPs) evoked by moderate to intense sounds. We studied the spatial origins of AN CAPs evoked by 2- to 16-kHz tone bursts at several sound levels by slowly injecting kainic acid solution into the cochlear apex of anesthetized guinea pigs. As the solution flowed from apex to base, it sequentially reduced CAP responses from low- to high-frequency cochlear regions. The times at which CAPs were reduced, combined with the cochlear location traversed by the solution at that time, showed the cochlear origin of the removed CAP component. For low-level tone bursts, the CAP origin along the cochlea was centered at the characteristic frequency (CF). As sound level increased, the CAP center shifted basally for low-frequency tone bursts but apically for high-frequency tone bursts. The apical shift was surprising because it is opposite the shift expected from AN tuning curve and basilar membrane motion asymmetries. For almost all high-level tone bursts, CAP spatial origins extended over 2 octaves along the cochlea. Surprisingly, CAPs evoked by high-level low-frequency (including 2 kHz) tone bursts showed little CAP contribution from CF regions ≤ 2 kHz. Our results can be mostly explained by spectral splatter from the tone-burst rise times, excitation in AN tuning-curve “tails,” and asynchronous AN responses to high-level energy ≤ 2 kHz. This is the first time CAP origins have been identified by a spatially specific technique. Our results show the need for revising the interpretation of the cochlear origins of high-level CAPs-ABR wave 1.NEW & NOTEWORTHY Cochlear compound action potentials (CAPs) and auditory brain stem responses (ABRs) are routinely used in laboratories and clinics. They are typically interpreted as arising from the cochlear region tuned to the stimulus frequency. However, as sound level is increased, the cochlear origins of CAPs from tone bursts of all frequencies become very wide and their centers shift toward the most sensitive cochlear region. The standard interpretation of CAPs and ABRs from moderate to intense stimuli needs revision.

Hearing depends on glutamatergic synaptic transmission mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). AMPARs are tetramers, where inclusion of the GluA2 subunit reduces overall channel conductance and Ca2+ permeability. Cochlear afferent synapses between inner hair cells (IHCs) and auditory nerve fibers (ANFs) contain the AMPAR subunits GluA2, 3, and 4. However, the tetrameric complement of cochlear AMPAR subunits is not known. It was recently shown in mice that chronic intracochlear delivery of IEM-1460, an antagonist selective for GluA2-lacking AMPARs [also known as Ca2+-permeable AMPARs (CP-AMPARs)], before, during, and after acoustic overexposure prevented both the trauma to ANF synapses and the ensuing reduction of cochlear nerve activity in response to sound. Surprisingly, baseline measurements of cochlear function before exposure were unaffected by chronic intracochlear delivery of IEM-1460. This suggested that cochlear afferent synapses contain GluA2-lacking CP-AMPARs alongside GluA2-containing Ca2+-impermeable AMPA receptors (CI-AMPARs), and that the former can be antagonized for protection while the latter remain conductive. Here, we investigated hearing function in the guinea pig during acute local or systemic delivery of CP-AMPAR antagonists. Acute intracochlear delivery of IEM-1460 or systemic delivery of IEM-1460 or IEM-1925 reduced the amplitude of the ANF compound action potential (CAP) significantly, for all tone levels and frequencies, by > 50% without affecting CAP thresholds or distortion product otoacoustic emissions (DPOAE). Following systemic dosing, IEM-1460 levels in cochlear perilymph were ~ 30% of blood levels, on average, consistent with pharmacokinetic properties predicting permeation of the compounds into the brain and ear. Both compounds were metabolically stable with half-lives >5 h in vitro, and elimination half-lives in vivo of 118 min (IEM-1460) and 68 min (IEM-1925). Heart rate monitoring and off-target binding assays suggest an enhanced safety profile for IEM-1925 over IEM-1460. Compound potency on CAP reduction (IC50 ~ 73 μM IEM-1460) was consistent with a mixture of GluA2-lacking and GluA2-containing AMPARs. These data strongly imply that cochlear afferent synapses of the guinea pig contain GluA2-lacking CP-AMPARs. We propose these CP-AMPARs may be acutely antagonized with systemic dosing, to protect from glutamate excitotoxicity, while transmission at GluA2-containing AMPARs persists to mediate hearing during the protection.

Electrical stimulation of the mammalian efferent vestibular system (EVS) predominantly excites primary vestibular afferents along two distinct time scales. Although roles for acetylcholine (ACh) have been demonstrated in other vertebrates, synaptic mechanisms underlying mammalian EVS actions are not well-characterized. To determine if activation of ACh receptors account for efferent-mediated afferent excitation in mammals, we recorded afferent activity from the superior vestibular nerve of anesthetized C57BL/6 mice while stimulating EVS neurons in the brainstem, before and after administration of cholinergic antagonists. Using a normalized coefficient of variation (CV*), we broadly classified vestibular afferents as regularly- (CV* 0.1) and characterized their responses to midline or ipsilateral EVS stimulation. Afferent responses to efferent stimulation were predominantly excitatory, grew in amplitude with increasing CV*, and consisted of fast and slow components that could be identified by differences in rise time and post-stimulus duration. Both efferent-mediated excitatory components were larger in irregular afferents with ipsilateral EVS stimulation. Our pharmacological data show, for the first time in mammals, that muscarinic AChR antagonists block efferent-mediated slow excitation whereas the nicotinic AChR antagonist DHβE selectively blocks efferent-mediated fast excitation, while leaving the efferent-mediated slow component intact. These data confirm that mammalian EVS actions are predominantly cholinergic.

Endolymphatic hydrops is an enlargement of scala media that is most often associated with Meniere's disease, though the pathophysiologic mechanism(s) remain unclear. In order to adequately study the attributes of endolymphatic hydrops, such as the origins of low-frequency hearing loss, a reliable model is needed. The guinea pig is a good model because it hears in the low-frequency regions that are putatively affected by endolymphatic hydrops. Previous research has demonstrated that endolymphatic hydrops can be induced surgically via intradural or extradural approaches that involve drilling on the endolymphatic duct and sac. However, whether it was possible to create an endolymphatic hydrops model using an extradural approach that avoided dangerous drilling on the endolymphatic duct and sac was unknown. The objective of this study was to demonstrate a revised extradural approach to induce experimental endolymphatic hydrops at 30 days post-operatively by obliterating the endolymphatic sac and injuring the endolymphatic duct with a fine pick. The sample size consisted of seven guinea pigs. Functional measurements of hearing were made and temporal bones were subsequently harvested for histologic analysis. The approach had a success rate of 86% in achieving endolymphatic hydrops. The risk of cerebrospinal fluid leak was minimal. No perioperative deaths or injuries to the posterior semicircular canal occurred in the sample. The presented method demonstrates a safe and reliable way to induce endolymphatic hydrops at a relatively quick time point of 30 days. The clinical implications are that the presented method provides a reliable model to further explore the origins of low-frequency hearing loss that can be associated endolymphatic hydrops.

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.

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.

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.

There is a strong association between endolymphatic hydrops and low-frequency hearing loss, but the origin of the hearing loss remains unknown. A reduction in the number of cochlear afferent synapses between inner hair cells and auditory nerve fibres may be the origin of the low-frequency hearing loss, but this hypothesis has not been directly tested in humans or animals. In humans, measurements of hearing loss and postmortem temporal-bone based measurements of endolymphatic hydrops are generally separated by large amounts of time. In animals, there has not been a good objective, physiologic, and minimally invasive measurement of low-frequency hearing. We overcame this obstacle with the combined use of a reliable surgical approach to ablate the endolymphatic sac in guinea pigs and create endolymphatic hydrops, the Auditory Nerve Overlapped Waveform to measure low-frequency hearing loss (≤ 1 kHz), and immunohistofluorescence-based confocal microscopy to count cochlear synapses. Results showed low- and mid-(1-4 kHz) frequency hearing loss at all postoperative days, 1, 4, and 30. There was no statistically significant loss of cochlear synapses, and there was no correlation between synapse loss and hearing function. We conclude that cochlear afferent synaptic loss is not the origin of the low-frequency hearing loss in the early days following endolymphatic sac ablation. Understanding what is, and is not, the origin of a hearing loss can help guide preventative and therapeutic development.

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.

Background: The vestibular sensory-evoked potential (VsEP) is an electrical potential that provides a direct test of vestibular function in animals. VsEP recordings are carried out using subcutaneous stainless steel electrodes placed over the nuchal crest (noninverting), behind either the left or right pinna (inverting), and at the hip (ground). A noninvasive head clip is used to secure the head to a mechanical shaker for delivery of a linear vestibular stimulus measured in units of jerk (g/msec). Frequent repositioning of the noninvasive head clip and skin electrodes may be necessary during recording for particular protocols; however, the test-retest reliability of the VsEP response (latency, amplitude, and threshold) has not been determined. Purpose: The purpose of this study was to determine the possible effects of frequent repositioning of the noninvasive head clip and skin electrodes on VsEP response parameters (latencies, amplitudes, and thresholds). We hypothesize that the VsEP response will remain stable and reliable with such repeated measurements in a given animal across time. Research Design: Linear VsEP responses were recorded from ten C57 mice (ages: 2.45 mo ±0.20; weights: 17.94 g ±1.51). Two standard threshold protocols and four repeated VsEP measurements at +6 dB re: 1.0 g/msec were performed, with four selected time points of head clip repositioning. In addition, three novice investigators performed measurements of noninverting electrode placement and head clip positioning. Results: VsEP response latency, amplitude, and threshold means did not significantly change with frequent repositioning of the head clip and skin electrodes; however, increased variability was observed. Conclusions: The findings demonstrate that repositioning does not introduce significant changes in mean parameter values of the recorded VsEP response waveform; however, mean absolute difference calculations demonstrated that frequent repositioning increased response variance. For VsEP protocols requiring frequent repositioning, standardized electrode montage, optimal placement of the noninverting electrode at the nuchal crest, and increased sample size are suggested.

Electrocochleography (ECochG) has been used to assess Ménière's disease, a pathology associated with endolymphatic hydrops and low-frequency sensorineural hearing loss. However, the current ECochG techniques are limited for use at high-frequencies only (≥1 kHz) and cannot be used to assess and understand the low-frequency sensorineural hearing loss in ears with Ménière's disease. In the current study, we use a relatively new ECochG technique to make measurements that originate from afferent auditory nerve fibers in the apical half of the cochlear spiral to assess effects of endolymphatic hydrops in guinea pig ears. These measurements are made from the Auditory Nerve Overlapped Waveform (ANOW). Hydrops was induced with artificial endolymph injections, iontophoretically applied Ca2+ to endolymph, and exposure to 200 Hz tones. The manipulations used in this study were far smaller than those used in previous investigations on hydrops. In response to all hydropic manipulations, ANOW amplitude to moderate level stimuli was markedly reduced but conventional ECochG measurements of compound action potential thresholds were unaffected (i.e., a less than 2 dB threshold shift). Given the origin of the ANOW, changes in ANOW amplitude likely reflect acute volume disturbances accumulate in the distensible cochlear apex. These results suggest that the ANOW could be used to advance our ability to identify initial stages of dysfunction in ears with Ménière's disease before the pathology progresses to an extent that can be detected with conventional measures.

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

The gaze stabilization test (GST) is used not only in examining gaze stability required by daily life activities, but also in identifying unilateral or bilateral vestibular deficits. However, a computerized GST (CGST) is an expensive assessment, which cannot be commonly used in most clinics. Validation of low-cost and low-technical clinical tests is required to decrease health care costs. The purpose of this study was to measure the accuracy of a new GST (NGST) in a cohort of healthy young adults with no history of vestibular or balance disorders, as well as the test-retest reliability when re-assessed 5–7 days. Subjects identified a visual target while actively and passively performing head movements in the yaw plane at an initial screening velocity of 130 degs/sec. The main outcome was a strong positive correlation in both active and passive NGST head movement amplitude degree and head movement velocity. Passive head movements had good accuracy (85%) to identify healthy individuals with no history of vestibular or balance disorders. In addition, the NGST has good test-retest reliability in head movement amplitude degree (r=0.795) and head movement velocity (r=0.797) of passive NGST within two testing sessions.

Objective This study examined the clinical use of the computerized gaze stabilization test (GST) as a screener for falls. Design Cross-sectional, descriptive. Setting Tertiary medical center. Subjects Fifteen older community-dwelling adults with a history of falls and 15 controls without a history of falls were recruited for participation in the study. Main outcome measures Participants performed GST with yaw plane head movements. The GST velocity was measured and compared with the dynamic gait index (DGI). Receiver operating characteristic (ROC) curves and area under the ROC curve (AUC) identified GST velocity cut points for identification of fallers based on history of falls and as compared with DGI score. Results Our results suggested that GST can discriminate between individuals at risk for falls versus those not at risk. ROC analysis identified an AUC of 0.92 (≤ 100.5 degrees per second criterion value) for GST based on history of falls and an AUC of 0.85 (≤ 100.5 degrees per second criterion value) based on DGI for classifying falling risk. When GST and DGI scores were combined, the protocol identified an AUC of 1.0 (100% sensitivity, 100% specificity) for identifying falling risk. Conclusion There were significant head movement velocity differences from participants classified by history of falls and the DGI. Therefore, GST may serve as a potential falling risk assessment measure for older individuals with a history of falls. It is recommended that GST be used in a combined protocol with DGI to accurately identify individuals with falling risk rather than used in isolation.

Glutamate-mediated excitotoxicity might contribute to the pathogenesis of Huntington's disease and other polyglutamine repeat disorders. We used murine neocortical cultures derived from transgenic and knock-in mice to test the effect of expression of expanded polyglutamine-containing huntingtin on neuronal vulnerability to excitotoxins or other insults. Neurons cultured from mice expressing either a normal length (Hdh(Q20)) or expanded (Hdh(Q111)) CAG repeat as a knock-in genetic alteration in exon one of the mouse Hdh gene [Hum Mol Genet 8 (1999) 115] had similar vulnerability to N-methyl-D-aspartate (NMDA) and kainate-mediated excitotoxicity. These neurons also exhibited similar vulnerability to oxidative stress (24 h exposure to 10-100 microM paraquat or 1-10 microM menadione), apoptosis (48 h exposure to 30-100 nM staurosporine or 1 microM dizocilpine maleate (MK-801) and proteasome inhibition (48 h exposure to 0.3-3 microM MG-132). Neocortical neurons cultured from mice transgenic for an expanded CAG repeat-containing exon 1 of the human HD gene (Mangiarini et al., 1996, R6/2 line) and non-transgenic littermate controls also had similar vulnerability to NMDA and kainate-mediated excitotoxicity. These observations suggest that expression of expanded polyglutamine-containing huntingtin does not acutely alter the vulnerability of cortical neurons to excitotoxic, oxidative or apoptotic insults.