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Down-regulation of inhibition following unilateral deafening J.E. Mossop a , M.J. Wilson b , D.M. Caspary b , D.R. Moore a ; * a University Laboratory of Physiology, Parks Road, Oxford OX1 3PT, UK b Department of Pharmacology, Southern Illinois University Medical School, Spring¢eld, IL 62794-9230, USA Received 21 October 1999; accepted 17 February 2000 Abstract Physiological and neurochemical experiments described here suggest that unilateral deafening causes a reduction in inhibition in the adult gerbil inferior colliculus (IC) contralateral to the deafened ear. Multiple-unit recordings were made from single electrode penetrations in the IC prior to and directly after contralateral cochlear ablation. These recordings showed up to 60% increases in the proportion of sampled loci at which neural activity excited by ipsilateral stimulation was observed after the ablation. Novel excitatory responses were evident within minutes of the ablation. Western blotting for glutamic acid decarboxylase protein levels showed significant decreases in the IC contralateral to cochlear ablation, relative to those in the ipsilateral IC, at 24 h and 7 days survival after the ablation. Four hour or 1 year survival post-ablation did not produce significant contralateral/ipsilateral differences in relation to the control group. Taken together, these results suggest the presence of at least two, short-term mechanisms involved in the central response to cochlear removal, both of which appear to implicate a decreased inhibitory influence. One is a very rapid, stimulus-related, functional unmasking. The other is a more delayed reduction in the capacity of Q-aminobutyric acid synthesis in the IC. ß 2000 Elsevier Science B.V. All rights reserved. Key words: Deafness ; Cochlear ablation ; Inferior colliculus ; Auditory plasticity 1. Introduction It is now well established that experimental sensori- neural hearing losses can, paradoxically, result in long- term increases in the excitatory responses of central auditory neurons to sound stimulation either of an un- damaged contralateral ear or of intact parts of the dam- aged cochlea (e.g. Milbrandt et al., 2000). Neuron trac- ing studies have shown considerable, long-term rewiring of the brainstem that, at least in some cases, appears to occur coincidentally with, and may support the physio- logical e¡ects of the hearing loss (Nordeen et al., 1983; Moore, 1994). However, we have recently shown that signi¢cant increased excitation in inferior colliculus (IC; McAlpine et al., 1997) and auditory cortex (Moore et al., 1997) neurons occurs in adult animals that have had the contralateral cochlea surgically destroyed just hours before the recordings were obtained. Here, we show in the adult gerbil IC that the increased excitation occurs within just a few minutes of deafening the contralateral ear. This increase in the response of central auditory neurons to stimulation of the intact, ipsilateral ear seems to occur too rapidly to be explained by brain rewiring. One alternative mechanism for more rapid changes in neural activity is a change in the expression of neuro- transmitters and/or their receptors and intracellular sig- nalling pathways. Studies in several systems have shown an activity-dependent regulation of Q-aminobutyric acidergic (GABAergic) neurons (e.g. Hendry and Jones, 1986, 1988; Caspary et al., 1990; Garraghty et al., 1991). Based on rapid changes in GABA A receptor ex- pression following monocular deprivation (Hendry et al., 1990), down-regulation of GABAergic systems has been postulated as a contributing factor in short-term unmasking of novel receptive ¢elds in visual cortex (Jones, 1993). In the auditory system, hearing loss pro- duced by acoustic trauma or ototoxic drugs has also been shown to down-regulate GABAergic systems (Ab- 0378-5955 / 00 / $ ^ see front matter ß 2000 Elsevier Science B.V. All rights reserved. PII:S0378-5955(00)00054-X * Corresponding author. Tel.: +44 (1865) 272507; Fax: +44 (1865) 272469; E-mail: [email protected] Hearing Research 147 (2000) 183^187 www.elsevier.com/locate/heares

Down-regulation of inhibition following unilateral deafening

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Page 1: Down-regulation of inhibition following unilateral deafening

Down-regulation of inhibition following unilateral deafening

J.E. Mossop a, M.J. Wilson b, D.M. Caspary b, D.R. Moore a;*a University Laboratory of Physiology, Parks Road, Oxford OX1 3PT, UK

b Department of Pharmacology, Southern Illinois University Medical School, Spring¢eld, IL 62794-9230, USA

Received 21 October 1999; accepted 17 February 2000

Abstract

Physiological and neurochemical experiments described here suggest that unilateral deafening causes a reduction in inhibition inthe adult gerbil inferior colliculus (IC) contralateral to the deafened ear. Multiple-unit recordings were made from single electrodepenetrations in the IC prior to and directly after contralateral cochlear ablation. These recordings showed up to 60% increases in theproportion of sampled loci at which neural activity excited by ipsilateral stimulation was observed after the ablation. Novelexcitatory responses were evident within minutes of the ablation. Western blotting for glutamic acid decarboxylase protein levelsshowed significant decreases in the IC contralateral to cochlear ablation, relative to those in the ipsilateral IC, at 24 h and 7 dayssurvival after the ablation. Four hour or 1 year survival post-ablation did not produce significant contralateral/ipsilateral differencesin relation to the control group. Taken together, these results suggest the presence of at least two, short-term mechanisms involved inthe central response to cochlear removal, both of which appear to implicate a decreased inhibitory influence. One is a very rapid,stimulus-related, functional unmasking. The other is a more delayed reduction in the capacity of Q-aminobutyric acid synthesis in theIC. ß 2000 Elsevier Science B.V. All rights reserved.

Key words: Deafness; Cochlear ablation; Inferior colliculus; Auditory plasticity

1. Introduction

It is now well established that experimental sensori-neural hearing losses can, paradoxically, result in long-term increases in the excitatory responses of centralauditory neurons to sound stimulation either of an un-damaged contralateral ear or of intact parts of the dam-aged cochlea (e.g. Milbrandt et al., 2000). Neuron trac-ing studies have shown considerable, long-term rewiringof the brainstem that, at least in some cases, appears tooccur coincidentally with, and may support the physio-logical e¡ects of the hearing loss (Nordeen et al., 1983;Moore, 1994). However, we have recently shown thatsigni¢cant increased excitation in inferior colliculus (IC;McAlpine et al., 1997) and auditory cortex (Moore etal., 1997) neurons occurs in adult animals that have hadthe contralateral cochlea surgically destroyed just hours

before the recordings were obtained. Here, we show inthe adult gerbil IC that the increased excitation occurswithin just a few minutes of deafening the contralateralear. This increase in the response of central auditoryneurons to stimulation of the intact, ipsilateral earseems to occur too rapidly to be explained by brainrewiring.

One alternative mechanism for more rapid changes inneural activity is a change in the expression of neuro-transmitters and/or their receptors and intracellular sig-nalling pathways. Studies in several systems have shownan activity-dependent regulation of Q-aminobutyricacidergic (GABAergic) neurons (e.g. Hendry and Jones,1986, 1988; Caspary et al., 1990; Garraghty et al.,1991). Based on rapid changes in GABAA receptor ex-pression following monocular deprivation (Hendry etal., 1990), down-regulation of GABAergic systems hasbeen postulated as a contributing factor in short-termunmasking of novel receptive ¢elds in visual cortex(Jones, 1993). In the auditory system, hearing loss pro-duced by acoustic trauma or ototoxic drugs has alsobeen shown to down-regulate GABAergic systems (Ab-

0378-5955 / 00 / $ ^ see front matter ß 2000 Elsevier Science B.V. All rights reserved.PII: S 0 3 7 8 - 5 9 5 5 ( 0 0 ) 0 0 0 5 4 - X

* Corresponding author. Tel. : +44 (1865) 272507;Fax: +44 (1865) 272469; E-mail: [email protected]

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bott et al., 1999; Milbrandt et al., 2000). In a search forcellular mechanisms involved in the central auditoryresponse to contralateral deafening, we assayed, usingWestern blots, the level of glutamic acid decarboxylase(GAD, the synthesizing enzyme for GABA) in theadult gerbil IC at varying times after cochlear abla-tion.

2. Materials and methods

2.1. Inferior colliculus physiology

In IC recording experiments, multi-unit responses tomonaural, ipsi- and contralateral tone stimulation (100ms) were recorded using standard methods (McAlpineet al., 1997) during single microelectrode penetrations inketamine and xylazine anesthetized adult gerbils (n = 6).Anesthesia was induced with 2 ml/kg of a mixture of 45mg/ml ketamine and 1.8 mg/ml xylazine and maintainedby approximately 3

4 hourly injections (0.5 ml/kg) of thesame mixture. The microelectrode was inserted throughthe cerebellum and driven through the right IC, sam-pling activity every 50 Wm. Multi-unit responses weredigitally processed with locally written software (`Brain-ware' ; Dr. J. Schnupp), enabling the display of spikewaveforms, dot rasters, peristimulus histograms, andresponse areas on-line. For each recording site, a spikethreshold level was de¢ned above the background noiseso that only isolated spikes were recorded. Quantitativerecordings typically included the activity of 1^3 neu-rons.

A stimulus was considered `excitatory' if it producedspike rates, within a 30 ms window of the stimulusonset, that exceeded the spontaneous rate (de¢ned asactivity occurring 0.4^0.9 s after stimulus o¡set) onmore than one third of stimulus deliveries. At veryhigh levels of ipsilateral stimulation, when both earswere intact, apparent `excitation' was often seen at thefrequency producing the most sensitive, contralateralresponse (e.g. Fig. 1, 4 kHz). However, it seems likelythat this high threshold excitation was produced byacoustic cross-talk. For this reason, ipsilateral stimula-tion was classed as `excitatory' only if the minimumthreshold was within 40 dB of that for contralateralstimulation, a level determined from recordings of co-chlear microphonics in the gerbil (D. Hartley and D.Moore, unpublished observations).

At the end of the penetration, with the electrode insitu, the contralateral (left) ear was surgically ablated(see Tierney et al., 1997) and responses to ipsilateral(right ear) stimulation were recorded at that deepestelectrode site within 3^15 min of the ablation. Record-ings at other sites were obtained during gradual elec-trode withdrawal within the next few hours. Control

animals (n = 5) had sham ablations, involving surgicallyopening the left bulla, but leaving the cochlea intact.

2.2. GAD Western blotting

Cochlear ablations were performed on the left ear ofadult gerbils under ketamine and medetomidine anes-thesia (0.2 ml/kg of a 4:1 mixture of Domitor and Ke-taset). After 4 h (n = 6), 24 h (n = 7), 7 day (n = 7), or1 year (n = 5) survival, animals were killed by cervicaldislocation and decapitated. The brainstem was rapidlyexposed, and blocks of tissue containing either one orboth ICs were quickly removed and frozen at 380³C.Time elapsed from killing until freezing of the tissuewas typically about 2^3 min. Control animals (n = 6)were left with both cochleae intact.

For tissue processing, the IC samples were thawed,dissected further, if necessary, homogenized in 50 mMTris bu¡er, and centrifuged at 10 000 rpm for 10 min.50 Wg of the resulting soluble fraction, containing thecytosolic fraction of the tissue, was electrophoresed ona 12% acrylamide gel. Proteins were then transferred tonitrocellulose paper (LKB NovaBlot, 80 mA for 3 h)and blocked for 1 h in 5% weight per volume skim milkpowder, 1 mM EDTA and 0.2% Triton X-100 in phos-phate bu¡ered saline. Blots were incubated overnight at4³C in anti-GAD antisera, washed ¢ve times for 10 mineach wash in the blocking solution, and then incubatedfor 1 h in the secondary antibody (horseradish peroxi-dase-conjugated goat anti-mouse IgG). Followingwashes in Tris bu¡er, the secondary antibodies werevisualized using an ECL Western blotting analysis sys-tem, and quanti¢ed using a GS-250 Phosphor Imagersystem (Bio-Rad). For statistical analysis of the result-ing optical density measures, the ratio of the densities inthe left and right ICs for individual animals was com-

Fig. 1. Physiological unmasking. Data from the deepest recordinglocation in one animal (gerbil 97119) showing response areas pre-and post-ablation. The post-ablation records were obtained within12 min of the contralateral cochlear ablation. The diameter of eachdata point is proportional to the number of spikes (corrected forspontaneous activity, see Section 2) during an ipsilateral stimulus ofthe indicated frequency and level. Darker ¢lled points indicate exci-tation (response level higher than spontaneous) and lighter ¢lledpoints indicate response suppression.

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puted, and the group means were compared using aone-way ANOVA (SPSS) and two-sided Dunnettpost-hoc analysis. The Dunnett analysis compared eachexperimental group with the control group.

3. Results

3.1. Inferior colliculus physiology

Recordings made within minutes of the contralateralcochlear ablation generally showed strong ipsilaterallyevoked excitation where, prior to the ablation, therehad been a mixture of suppression and weak excitation.Fig. 1 shows an example of multi-unit recordings, madein response to ipsilateral stimulation, at the same elec-trode site, just before and, again, 12 min after contra-lateral cochlear ablation. The size of each data point isproportional to the response strength, relative to thespontaneous activity level. Here, the pre-ablation ipsi-lateral response was weak, high threshold, and showedsuppression below spontaneous activity levels for somestimuli. The post-ablation response showed, by con-trast, strong, low threshold excitation, with no stimu-lus-related suppression.

From our total sample of recording sites (n = 75; Fig.2), we identi¢ed 30 sites that were excited ipsilaterallyafter the ablation, but that had been unresponsive priorto the ablation. About two thirds of these sites showedstrong ipsilateral excitation organized into V-shaped re-sponse areas, as exempli¢ed by Fig. 1. Overall, the per-cent of ipsilaterally excited recording loci increased sub-

stantially in all six experimental gerbils, whereas controlanimals showed no systematic e¡ect of sham surgery onipsilateral excitation levels (Fig. 2).

3.2. GAD

The ratio of GAD in the contralateral (right) IC tothat in the ipsilateral (left) IC (Fig. 3) at 24 h and 7days after the left cochlear ablation was signi¢cantly(F4;26 = 3.0, P6 0.05) less than that found in the bilat-erally intact control animals. In contrast, at the shortest(4 h) and longest (1 year) post-ablation survival periodsexamined, there was no reduction in GAD. In boththese groups, and in the control group, at least halfthe animals had lower GAD levels in the contralateralthan in the ipsilateral IC (Fig. 3). In the 24 h and 7 day

Fig. 2. Changes in ipsilateral excitation ^ group data. Each animal is represented by a pair of histogram bars showing the proportion of IC re-cording locations at which ipsilateral stimulation evoked excitatory responses prior to (Pre) and following (Post) acute ablation or sham abla-tion (control) of the contralateral cochlea.

Fig. 3. GAD data. Histogram bars show the mean ( þ S.E.M.) ratioof GAD levels in the IC contralateral (right) and ipsilateral (left) tothe ablated cochlea, as measured by optical density of the Westernblots. Fractions next to each bar show the number of gerbils (of thetotal) that had higher GAD levels in the contralateral (right) IC.

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groups, however, nearly all animals (11/14; binomialP6 0.03) had lower GAD levels in the contralateral IC.

4. Discussion

These experiments suggest that at least two distinctmechanisms are involved in the increased responsive-ness of IC neurons following contralateral cochlearablation in adult animals. One appears to be a veryrapid, stimulus-related, `unmasking' of ipsilateral exci-tatory responses from inhibition that is somehow nor-mally driven by the presence of the contralateral ear.Short-term increases in the excitability of central audi-tory neurons following hearing loss have been shownpreviously (McAlpine et al., 1997; Popelar­ et al., 1994;Reale et al., 1987; Salvi et al., 1990; Szczepaniak andMÖller, 1996; Willott and Lu, 1982). However, thosestudies have used deafening procedures (acoustic trau-ma, ototoxicity) that have sub-total and/or non-station-ary e¡ects on the cochlea, or they have not examinedthe excitability of neurons immediately after performingthe deafening. Thus, the very rapid physiologicalchanges shown here following cochlear removal wouldnot have been observable in those studies.

The second mechanism, suggested by the GAD blot-ting results, is a more delayed reduction in the capacityof the GABA synthesizing machinery in the IC contra-lateral to the cochlear removal. Similar changes havebeen shown in the visual system following monoculareye removal (Hendry and Jones, 1988), where the num-ber of GAD-immunoreactive neurons in deprived-eyecolumns in primary visual cortex was reduced by asmuch as 50% within 4 days of eye removal. In the IC,studies have shown decreased GABA following drug-induced deafening (Bledsoe et al., 1995) and decreasedGAD following traumatic acoustic exposure (Abbott etal., 1999; Milbrandt et al., 2000). The release and up-take of GABA in the adult guinea pig brainstem andmidbrain during 2^145 days after unilateral ossicularremoval or cochlear ablation have recently been studiedin detail by Suneja et al. (1998). They found, at 5 daysafter ablation, an increase in the release of [14C]GABAin the IC contralateral to the ablated cochlea. This wasfollowed by a return to normal levels (by 59 days) and asubsequent, further increase. They reported no changein GABA release at any time in the ipsilateral IC. Up-take of GABA was una¡ected for the ¢rst 59 days andsubsequently decreased. As in the previous physiologi-cal studies cited above, the earlier time course of thechanges was not examined in these GABA studies.However, it would appear that the pre- and post-syn-aptic components of GABA synthesis and action fol-lowing hearing loss are complex and strongly time-de-pendent. Both GAD and GABA levels have, under

speci¢c circumstances in other brain systems, beenquantitatively related to each other, and to the levelof physiological activity (Abbott et al., 1999).

The current results must be interpreted carefully. Theimplication of reduced GAD levels in the contralateralIC rests upon two assumptions that may not be ¢rmlygrounded. The ¢rst assumption is that cochlear removaldecreased the level of GAD in the contralateral ICwhile leaving GAD levels in the ipsilateral IC relativelyunchanged. The changes shown in Fig. 3 are assumedto re£ect simply a drop in the contralateral GAD levelrather than more complicated e¡ects involving bothICs. However, there is no ¢rm evidence to show thatpost-ablation GAD levels are changed only in the ICcontralateral to the ablation, or that the levels do notrise in other nuclei (Suneja et al., 1998). In addition, thegerbil has extensive, functional IC^IC reciprocal con-nections, via the commissure of the IC (Moore et al.,1998). These, and several other known a¡erent path-ways to the IC (e.g. that from the contralateral dorsalnucleus of the lateral lemniscus; Schwartz, 1992) maymake an extrinsic contribution to observed changes inthe levels of GAD and GABA in the IC.

The second assumption also relates to the signi¢cantdrop in contralateral GAD levels found at 24 h and 7days after the cochlear ablation. Overall, the controlgroup produced a mean ipsilateral/contralateral ratioof 1.2. Without this control asymmetry, the GAD ratiodata from the longer survival groups might not haveachieved signi¢cance. However, three of the six controlanimals showed a relatively higher level of GAD in thecontralateral than in the ipsilateral IC, suggestive ofindividual variability rather than actual asymmetry.No right^left asymmetries were noted in a previouslypublished study of GAD immunostaining in the IC ofthe gerbil (Roberts and Ribak, 1987). In addition, it hasbeen found that unilateral deafening does not changethe level of evoked neural activity in the IC ipsilateralto the deafened ear (Nordeen et al., 1983; McAlpine etal., 1997), so it would appear that, if there were achange in the level of GAD/GABA in the ipsilateralIC, it might not be physiologically signi¢cant. Even ifthe levels of GAD/GABA in the ipsilateral IC wereuna¡ected by the deafening, we do not know whetherthe relatively small decreases in GAD in the contralat-eral IC were physiologically signi¢cant. It may be rele-vant in this context that, following a very long period ofdeafness, the GAD symmetry in the two ICs was re-stored, whereas previous physiological data (McAlpineet al., 1997; Moore et al., 1997) have shown that en-hanced excitation from the ipsilateral ear persists.

Overall, the results presented here suggest that inhib-itory processes in the central auditory system are rap-idly in£uenced by unilateral deafening. Previous obser-vations of enhancement of excitation driven by the

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intact ear (McAlpine et al., 1997) may derive from aseries of changes in inhibitory in£uences in and on neu-rons in the IC ^ a very rapid release of functional in-hibition, followed by a reduction of inhibitory neuro-transmitter synthesis.

Acknowledgements

The research in this study was supported by student-ships to J.E.M. from NSERC (Canada) and the OxfordMcDonnell-Pew Centre in Cognitive Neuroscience, byProgramme Grant G9631094 from the MRC (UK) toD.R.M., and by Grant NIDCD DC00151 from theNIH (US) to D.M.C. Anne Russell provided valuableassistance with surgery and tissue preparation.

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