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Neuroscience and Biobehavioral Reviews 35 (2011) 2114–2116

Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews

journa l h o me pa g e: www.elsev ier .com/ locate /neubiorev

eview

he ongoing balance of cortical excitation and inhibition during earlyevelopment

ing Xionga, Xiuping Liub,c, Lei Hana, Jun Yanc,∗

Department of Neurobiology, Third Military Medical University, Chongqing, PR ChinaHealth Sciences Centre, Hebei University, 342 Yuhua Eastern Road, Baoding, Hebei 071000, PR ChinaDepartment of Physiology and Pharmacology, Hotchkiss Brain Institute, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1

r t i c l e i n f o

rticle history:eceived 17 September 2010eceived in revised form 8 February 2011ccepted 8 February 2011

a b s t r a c t

Two papers recently published in Nature propose that the balance between excitation and inhibitionis important for the maturation of cortical function. Their conclusions however, are contradictory; onestudy suggests that balance is established before hearing onset, whereas the other proposes that balanceis established after hearing onset. We carefully examined the data and found that the differences betweenthe two groups are less dramatic than they first appear. Despite their methodological differences, both

eywords:uditory cortexevelopmentxcitationnhibitioneceptive field

studies provide evidence that an ongoing balance between cortical excitation/inhibition accounts for thematuration and refinement of cortical function during early development.

© 2011 Elsevier Ltd. All rights reserved.

n vivo patch clamp

ontents

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2116References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2116

Similar to other sensory cortices, the auditory cortex under-oes drastic remodelling immediately after hearing onset. Prior toensory experience, some function-specific regions and neuronaldentities of the sensory cortex already emerge, such as the ocularominance of the visual cortex and tonotopy-like organization ofhe auditory cortex (Hartmann et al., 1997; Rakic, 1977; Shepherdt al., 1997). These precursors of functional specifications and neu-onal identities suggest that the neural wiring of the sensory cortexnd its thalamocortical innervation are mostly established beforehe maturation of sensory organs (Hoffpauir et al., 2009; Zhao et al.,

period (Berardi et al., 2000; Yan, 2003; Hensch, 2004; Shideler andYan, 2010). The neuronal RF plasticity of the auditory cortex dur-ing the critical period is typically characterized by a sharp decreasein response thresholds, a quick shift in tuning from low to highfrequencies and optimal sharpening in excitatory RF or frequencytuning (Zhang et al., 2001).

The mystery of how neuronal RFs of the sensory cortex are dras-tically altered and quickly shaped into adult form during the criticalperiod is very challenging. Although the decisive role of the tha-lamocortical system is well established (Sur and Leamey, 2001;

009). Sensory experience quickly remodels the primordial sensoryortex into distinct multi-functional areas and the adult form ofhe functional organization and neuronal receptive field (RF) of theensory cortex exhibits in a short period, i.e., the so-called critical

∗ Corresponding author. Tel.: +1 403 220 5518; fax: +1 403 270 3145.E-mail address: juyan@ucalgary.ca (J. Yan).

149-7634/$ – see front matter © 2011 Elsevier Ltd. All rights reserved.oi:10.1016/j.neubiorev.2011.02.005

Yan, 2003; Feldman, 2009), a growing body of evidence suggestthat the development of cortical inhibition is concomitant with thematuration of cortical function and that cortical inhibition playsa crucial role in the functional refinement of the sensory cortex(Hensch, 2005; Kanold and Luhmann, 2010). Earlier studies thatexamined brain slice preparations confirm that inhibitory neuronsreadily develop and that the relative strength of inhibitory and

excitatory synapses is regulated in the developing cortex (Shawand Scarth, 1992; Galarreta and Hestrin, 1998). Recent studies inthe visual and somatosensory cortices have suggested that corticalinhibition not only enables drastic plasticity but that it also adjusts

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r even initiates the onset of the critical period in cortical devel-pment. The impact of cortical inhibition is likely associated withhe development of sensory acuity (Hensch, 2005; Feldman, 2009;ale et al., 2010; Southwell et al., 2010). The discovery of the crucialole of inhibitory circuitry in cortical plasticity during the criticaleriod has led to ongoing investigations of the prevalent model, i.e.,hat the maturation and refinement of the sensory cortex is definedy the balance of excitatory and inhibitory circuitry (Hensch andagiolini, 2005; Maffei and Turrigiano, 2008).

In the auditory cortex, inhibition is also known to be importantor cortical processing of sound information (Sutter et al., 1999;oftus and Sutter, 2001; Metherate et al., 2005) whereas the cellularechanisms responsible for inhibition remain poorly understood.

state-of-art technique, in vivo whole cell patch clamp, is capa-le of observing sound-driven membrane potential and recordinghe excitatory and inhibitory RFs in the same neuron; it allowss to examine the cellular mechanism of the frequency tuningr RF of auditory cortical neurons. That excitatory and inhibitoryFs of a single neuron in the adult primary auditory cortex areostly overlapped in the frequency domain is confirmed. The bal-

nce between excitation and inhibition appears essential (Wehrnd Zador, 2003; Zhang et al., 2003). Investigations that workowards clarifying a precise time-frame for the initiation of excita-ory/inhibitory circuitry as well as identifying their mechanisms areequired.

Two papers recently published in Nature addressed these issues.he studies by Sun et al. and Dorrn et al. examined excitatorynd inhibitory RFs of cortical neurons at different postnatal days,ncluding postnatal days 11–13 when hearing begins, and at p80,

hen the auditory cortex is considered mature. In vivo whole-cellatch clamp recordings of neuronal RF (frequency tuning) of therimary auditory cortex in anesthetised rats were used. The corti-al RFs were sampled with a series of pure tone bursts in which therequency ranged from 0.5 to 32 kHz or 0.5 to 64 kHz. The amplitudef tone bursts was set at specific sound pressure levels that variedetween the two studies, an important distinction that we discuss

n detail below. The excitatory RF of a given cortical neuron wasecorded by maintaining the cell membrane potential at −80 mVnd the inhibitory RF, by maintaining the membrane potential at

mV. The excitatory and inhibitory RFs were compared using eitherross-correlation or mismatch index (Dorrn et al., 2010; Sun et al.,010; King, 2010).

The data from both studies confirm that the balance betweenxcitation and inhibition plays a crucial role in the functional matu-ation of the rat primary auditory cortex during early development.un et al. conclude that the balance between excitation and inhibi-ion is already established in the primary auditory cortex beforeearing onset. The quick remodelling of cortical RF into adult-

orm is mostly dependant on a fine adjustment of excitatory inputtrengths rather than the balance of excitation and inhibition prioro auditory experience (Sun et al., 2010). In marked contrast, Dorrnt al. conclude that the maturation of cortical RF is determined byrogressive refinement of intracortical inhibition. In other words,he balance of cortical excitation and inhibition is gradually estab-ished after hearing onset (Dorrn et al., 2010).

The conclusions reached by the two investigating groups appearontradictory at first glance. The authors of this review comparedoth studies for a possible explanation/s. We noted major differ-nces in the experimental methods also addressed by Dr. Froemken his review in the same issue and by Dr. Andrew King in his recenteview (King, 2010). Our group additionally observed a significantifference in the tone intensity used for sampling the excitatory

nd inhibitory RFs or frequency tunings. Sun et al. sampled theunings at 20 dB above the minimum threshold of individual neu-ons whereas Dorrn et al. sampled with an identical sound intensity70 dB SPL) for all studied neurons. Is the difference significant? A

ioral Reviews 35 (2011) 2114–2116 2115

fact regarding the maturation of the central auditory system is thatdramatic RF plasticity during the critical period occurs not only inthe auditory cortex but also in subcortical nuclei such as the mid-brain (Yan, 2003). This suggests that a major factor triggering thechange in cortical RFs is a progressive increase in thalamocorti-cal synaptic input in the first 2–3 days after hearing onset (Zhanget al., 2001; de Villers-Sidani et al., 2007). Accordingly, the strengthof thalamocortical input directed at a given cortical neuron dur-ing the postnatal period was relatively consistent in the study bySun et al. but it would have progressively increased in the study byDorrn et al. The inconspicuous difference in tone intensity settingcould distort, to a large degree, the difference in sampled frequencytuning or RF of cortical neurons during the critical period of earlydevelopment. We suggest that this is a likely explanation for theconflicting conclusions.

It is known that the earliest tone-evoked response in the primaryauditory cortex can be recorded at P11–P13 in the same speciesof the rat (Zhang et al., 2001; Chang et al., 2005; de Villers-Sidaniet al., 2007). Therefore, data sampled from P13 to P16 appear to bemost important. Sun et al. confirm that neuronal RFs of the auditorycortex undergoes the largest alteration during this period, particu-larly in the response threshold, as demonstrated with in vivo wholecell patch-clamp recording (Figs. 1c and 2a in Sun et al., 2010).They recorded well-tuned excitatory and inhibitory RFs with a highresponse threshold at P13; the excitation and inhibition frequencytunings were well matched (Fig. 1 in Sun et al., 2010). In contrast,Dorrn et al. recorded well-tuned excitatory RFs but a poorly tunedinhibitory RF at 70 dB SPL; the excitation and inhibition frequencytunings were less correlated (Fig. 1a in Dorrn et al., 2010). Sincea response threshold of 70 dB SPL was attained by cortical neu-rons during this period and that the response threshold of corticalneurons varied from neuron to neuron (Fig. 1a in Sun et al., 2010;Chang et al., 2005; de Villers-Sidani et al., 2007), it is not surpris-ing that the excitation/inhibition correlation showed considerablevariation (Fig. 1c in Dorrn et al., 2010).

It is also important to note that sampling tunings at higher toneintensity levels can reliably confirm the correlation of excitatoryand inhibitory tunings after P16, possibly owing to less changein thalamocortical input strength, i.e., the minimum threshold ofcortical neurons (Fig. 3a in Sun et al., 2010). A progressive improve-ment of inhibition was supported by data sampled at 70 dB SPL(Fig. 1c in Dorrn et al., 2010) and at 20 dB SPL above the minimumthreshold of a given neuron (Fig. 3c in Sun et al., 2010) but not atthe threshold level (Fig. 3b in Sun et al., 2010).

Our analysis of both sets of data shows that excitation andinhibition is balanced before hearing onset. The balance betweenexcitatory and inhibitory circuitry may influence the constructionof tonotopy-like organization of the auditory cortex prior to audi-tory experience. The “pre-balance” is likely broken immediatelyafter hearing onset because of the increased strength in excitatorythalamocortical input. The balance between excitation and inhi-bition however, appears to be ongoing at later stages, a processsimilar to what is seen in the developing visual cortex (Hensch andFagiolini, 2005).

Generally, the balance should be dynamic – inhibition shouldfollow the change in excitation. Balanced inhibition could be impor-tant for maintaining a suitable level of the activity or responses ofcortical neurons, either before or after the hearing onset. Previ-ous morphological findings of cortical GABAergic (�-aminobutyricacid) neurons and synapses also suggest that inhibitory circuitryis already established before sensory onset and that the propor-tion of GABAergic neurons and synapses over the total neurons

and synapses is somewhat consistent over embryonic developmentalthough the maturation of the inhibitory cortical system occurslater than that of the excitatory system (Micheva and Beaulieu,1997). The findings by Sun et al. are likely indirect evidence of

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pre-balance” since data were immediately collected after hearingnset.

In conclusion, measuring the balance of tone-driven excita-ion and inhibition tunings before hearing onset is a daunting ifot impossible task. Since inhibitory tuning of cortical neurons

s likely a consequence of feedforward modulation through cor-ical GABAergic neurons, some useful data might be obtained by

easuring excitatory and inhibitory input/output functions of cor-ical neurons with focal electrical stimulation of the thalamus,ither in vivo or in vitro. A recent study in mouse thalamocorticallice preparations suggests that auditory thalamocortical strengthncreases from P2 to P13 (Zhao et al., 2009). If the excitationnd inhibition is balanced before hearing onset, the relationshipetween excitatory and inhibitory input/output functions shoulde similar before and after hearing onset. This clarification wouldllow us to examine the impact of thalamocortical input strengthsound intensity) on the ongoing balance between cortical inhibi-ion and excitation.

cknowledgements

This work is supported by the China-Canada Joint Healthesearch Initiative Grant of the National Natural Science Foun-ation of China (30770681-30911120490) in partnership withanadian Institutes of Health Research (CCI-102927), the Alberta

nnovates – Health Solutions, and the Excellent Going-Abroadxperts Training Program of the Hebei Province of the PRhina.

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