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obliterate the details of the individual ele-ments when they are sparsely arrayed.

If texture statistics and individual iden-tities can be available simultaneously in lessdense arrays, why is access to individualidentity abandoned beyond a certain den-sity? Could there be any utility to thecrowding effect that prevents access to localdetail? Perhaps texture statistics and the seg-mentation they support are more efficientwhen no local item identities clutter theregion to be analyzed. There is no evidencefrom Ariely3 or Parkes et al.2 to indicate adisadvantage when items in the array canbe individually accessed, but this compar-ison has not been tested explicitly. It is thusunclear whether crowding is advantageousfor texture processing or simply anunavoidable limit that happens to permittexture analysis to continue unimpaired.But although we do not yet know whycrowding works as it does, we can still askhow it works. It might be lateral maskingat a level beyond the early levels where pool-ing and aftereffects are mediated. Or itmight be the limited spatial resolution ofattention1—the inability to pick up indi-vidual items if more than one item fallswithin the smallest ‘window’ of attentionavailable at that eccentricity. The details ofthis process remain to be discovered.

Whether or not ensemble statistics likethe average orientation are more accuratein crowded displays, their high degree ofaccuracy is intriguing. Parkes et al.2

demonstrate that the ensemble average is

‘pop out’ in the reported experiments.One answer may be that even when thepatches of oriented grating differ marked-ly in orientation, they all have identical,circular Gaussian envelopes. Perhaps thislevel of similarity is enough for the visu-al system to treat the set of items as a tex-ture of relatively homogeneous elements.Further work would help to clarify this.

The work by Parkes et al. bridges twoareas of research: crowding and texture per-ception. Crowding research has longdemonstrated the inability to access iden-tity in dense arrays of similar items but hasnot evaluated how the resulting texturesform from and absorb the individual iden-tities. Research on the discrimination andsegregation of textures has examined thenature of ensemble statistics of arrays buthas ignored whether or not the array itemsare individually accessible. Parkes et al.2

now show that crowded information is pre-served in accurate ensemble statisticswhether or not access to individual items ispossible. Their work is an important steptoward revealing the underlying linksbetween the mechanisms of crowding andtexture segmentation.

1. He, S., Cavanagh, P. & Intriligator, J. Nature383, 334–338 (1996).

2. Parkes, L., Lund, J., Angelucci, A., Solomon, J. A., & Morgan, M. J. Nat. Neurosci. 4,739–744 (2001).

3. Ariely, D. Psychol. Sci. 12, 157–162 (2001).

4. Morgan, M. J., Watamaniuk, S. N. & McKee, S. P. Vision Res. 40, 2341–2349 (2000).

not a rough estimate but a highly accuratevalue computed over the orientation sig-nals. If the goal of the ensemble statisticwere simply to compress the descriptionof the details in a region, there is no obvi-ous reason to make this description soaccurate. Certainly ensemble statistics maybe useful to characterize a surface as onematerial or another (grass, wood, water,hair, textiles and so forth), and the moreprecise the characterization, the better theclassification of surface materials.

But ensemble statistics may also sup-port a more important function: detect-ing deviants, identifying items that do notbelong. Computationally this is a verycomplex task, as each item needs to becompared to all the others. Any ensemblestatistic that is computed automaticallywill simplify this task enormously. Andhere, a more accurate ensemble statisticallows for more sensitive detection ofdeviance from the ensemble properties.

Deviation from the crowd pops out; itbreaks crowding. This may be the mostimportant function of ensemble statistics:rapid identification of deviant items withenormous savings in computational com-plexity. At least here the precision of theaverages discovered by Parkes et al.2 makethe most sense, given the importance ofdetecting odd items that do not belong inthe group. On this account, readers famil-iar with the visual search literature mightbe puzzled why the extremely deviant ori-entation (as much as 90 degrees) did not

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A new form of feedback atthe GABAA receptorKevin Staley and Roderic Smith

GABA is inhibitory in adults, but it is excitatory in younganimals. A recent study shows that activation of the GABAAreceptor itself may promote this developmental switch.

Although GABA is the main inhibitoryneurotransmitter in the adult central ner-vous system, there are several circumstancesin which GABAA receptor activation excitesneurons instead of inhibiting them. In the

immature nervous system, for example,GABA is universally excitatory. Then, justas synaptic activity develops to the pointthat runaway excitation seems imminent1,GABA becomes inhibitory2. GABA man-ages this last-minute functional turnaboutby an intriguing activity-dependent changein the chloride reversal potential, describedin a recent paper in Cell by Ganguly, Schin-der and colleagues in the Poo laboratory3.

The heavy lifting of synaptic signaltransduction is accomplished by ions dri-ven through open channels by the con-centration and voltage differences acrossthe neuronal membrane. This drivingforce is conveniently summarized by thereversal potential, where the voltage andconcentration differences balance, and nonet ionic flux occurs. For cationic currents,the reversal potentials are well-behavedround numbers: 0 mV for excitatory cur-rents and –100 mV for inhibitory potassi-um currents. In contrast, the inhibitoryanionic currents that flow through theGABAA receptor channel have a small netdriving force, so the GABAA reversalpotential is just a few millivolts more neg-ative than a typical resting membranepotential of –65 mV (Fig. 1).

The reversal potential for chloride, themost permeant and plentiful anion, is set bya chloride exporter called KCC2 that derivesits energy from the potassium gradient4, aswell as a chloride importer, called NKCC1,

The authors are at the University of ColoradoHealth Sciences Center, Box B182, 4200 East9th Avenue, Denver, Colorado 80262, USA. e-mail: kevin.staley@uchsc.edu

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that is driven by both sodium and potassi-um gradients5. It would seem that the mosteffective inhibitory driving force would bedeveloped if the cell were to shut off NKCC1completely, and upregulate KCC2—so thatthe chloride reversal potential would cometo equilibrium with EK at –100 mV. One rea-son not to do this is that GABA might hyper-polarize neurons to the point of activatingdepolarizing currents, such as IH (ref 6). Butperhaps the key advantage to a small drivingforce for GABAA receptor currents is that by making minor adjustments to theKCC2/NKCC1 pumping system, neuronscan change the intracellular chloride con-centration by a few millimolar, which isosmotically acceptable—yet sufficient toswitch the role of GABA between excitationand inhibition (Fig. 1).

During development, net active chlo-ride transport is inward, so that anionsflow out of the neuron when the GABAAchannel is opened. This depolarizes themembrane strongly enough to activatevoltage-dependent calcium channels2 andrelieve the Mg2+ block of the NMDAreceptor3. The resultant calcium transientshave important effects on the growth anddevelopment of the neuron, but as exci-tatory glutamatergic synapses becomemore plentiful, GABA needs to becomeinhibitory in a hurry to stabilize the newneural networks.

Ganguly, Schinder et al.3 studied thisfunctional transition of GABA in culturedrat hippocampal neurons that were platedat a time when GABA was excitatory (E18,

What are the elements of the trans-duction cascade between the calcium tran-sient and the persistent increase in KCC2expression? One clue may lie in the neu-ronal specificity of KCC2 expression. Abinding site for neuronal-restrictive silenc-ing factor was recently discovered on theKCC2 gene8; it is possible that the calciumtransients trigger the life-long increase inKCC2 by initiating the events that removethis negative control of KCC2 expression.

What characteristics of the GABA-trig-gered calcium transients are necessary forinitiating (or propagating) the signal toincrease KCC2 expression? After all, calci-um is also admitted during glutamatergicreceptor activation and action potentials.However, blocking these events did notchange the evolution of the GABAA rever-sal potential, so there must be somethingabout the temporal or spatial properties ofthe GABA-gated calcium transients that areimportant in regulating KCC2 expression.Although elevation of extracellular potas-sium also accelerated the negative shift inthe GABA reversal potential, it is difficultto know whether this was due to the samesignaling cascade as set in motion byGABA, or whether KCC2 was upregulatedby another mechanism in response to achronic reduction of its energy supply, thetransmembrane potassium gradient.

Once KCC2 expression is increased, itremains high for the life of the animal9.Are the GABA-gated calcium transientsthat occur during the neonatal period sole-ly responsible for this life-long alterationin KCC2 expression? In the synaptic plas-ticity literature, altered protein expressiondue to postsynaptic calcium transients hasonly been demonstrated for a few hoursafter the initiating calcium signal10, so life-long alteration in KCC2 expression andGABA response may represent a newrecord for the longest-term activity-depen-dent changes in a synaptic response.

Many might argue that the change inKCC2 expression is a developmental phe-nomenon, not an example of synaptic plas-ticity, but several observations suggest thatthe genes coding for KCC2 and NKC1 inadult neurons are not simply ‘housekeep-ing’ genes with fixed levels of expression.For one thing, in adult neurons the GABAAreversal potential can undergo long-termshifts back into the excitatory range,although the required stimuli are fairly dra-matic: trauma or heat shock11. For anoth-er, the GABA reversal potential variessubstantially from neuron to neuron, andthe more the chloride transport system isstressed (for example by prolonged GABAAreceptor currents), the more striking these

two days before birth). Using calcium flu-orescence imaging, perforated patch record-ings and RNase protection assays, theydemonstrated a change in both KCC2expression and the GABA reversal poten-tial that corresponded to the timing ofGABA changes observed in acute prepara-tions7. All neurons were excited by GABAfour days after plating, but by day eight,most neurons had an inhibitory responseto GABA. The intriguing finding was thatwhen GABAA receptors were blocked, thechanges in both KCC2 expression and theGABA reversal potential were significantlydelayed; when exogenous GABAA receptoragonists were added to the culture, the tran-sition was accelerated. Although the GABAtransition was unaffected by blockade ofaction potentials and glutamate receptors,the transition to inhibition was preventedby L-type calcium channel antagonists.

Thus we have the provocative storythat as synapses develop, GABAA recep-tor activation depolarizes the membrane,triggering calcium transients, which leadto an increase in the expression of thechloride exporter KCC2. The activity ofthis exporter reverses the transmembranechloride gradient—with the result thatGABA becomes an inhibitory transmitter(Fig. 2). Thus, the seemingly last-minutetiming of the functional transition ofGABA is accomplished by allowing thelevel of activation of GABAA receptors toregulate the GABAA reversal potential. Aswith any good story, we are left with morequestions than answers.

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Fig. 1. A little chloride goes a long way. The Nernst equation relates the transmembrane chlo-ride concentration gradient to the reversal potential. This relationship is very steep at physiolog-ical concentrations of intra- and extracellular chloride, so a change in the intracellular chlorideconcentration of only about 12 mM is sufficient to cause the GABAA reversal potential to changefrom below the resting membrane potential to above both the resting membrane potential andthe action potential threshold. HCO3

– also permeates the GABA receptor channel, whichreduces the critical shift in intracellular chloride needed to change the GABA effect from inhibi-tion and excitation. For simplicity, Ganguly, Schinder et al. removed HCO3

– from the culturemedia, and the effects of HCO3

– on the GABA reversal potential are not depicted here.

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interneuronal differences become, sug-gesting that there are neuron-to-neurondifferences in chloride transport capaci-ty12,13 that may reflect ongoing variationsin KCC2 expression. Finally, studies sug-gest that KCC2 RNA and protein have theshort half-lives characteristic of highly reg-ulated expression systems7. Of course, ifKCC2 expression is plastic in the adult,additional mechanisms for refining itsexpression must be available, becauseGABA receptor-mediated synaptic activi-ty in the adult is inhibitory and does nottrigger calcium transients.

The finding that GABAA receptor activ-ity alters both KCC2 expression and theGABAA reversal potential raises thornyquestions as to the proximate causes of theGABA reversal potential. If increased GABAactivity increases KCC2 expression, and thelevel of KCC2 expression is the major deter-minant of ECl, then ECl would be expectedto become closer to its theoretical maxi-mum, EK (rather than simply reaching theadult value of ECl). There are of courseother determinants of the chloride reversalpotential, such as NKCC1, but exportingchloride through KCC2 at the same timethat chloride is being imported via NKCC1seems to be an exceptionally wasteful meansto set the chloride reversal potential. It maybe that negative feedback mechanisms limitthe maximum chloride transport capacity;the data of Ganguly, Schinder et al.3 do notaddress whether the KCC2 message levels

J. Biol. Chem. 271, 16245–16252 (1996).

5. Delpire, E. NIPS 15, 309–312 (2001).

6. Chen, K. et al. Nat. Med. 7, 331–337 (2001).

7. Rivera, C. et al. Nature 397, 251–255 (1999).

8. Karadsheh, M. F & Delpire, E. J. Neurophysiol.85, 995–997 (2001).

9. Clayton, G. H., Owens, G. C., Wolff, J. S. &Smith, R. L. Brain Res. Dev. Brain Res. 109,281–292 (1998).

10. Nayak, A., Zastrow, D. J., Lickteig, R.,Zahniser, N. R. & Browning, M. D. Nature394, 680–683 (1998).

11. van den Pol, A. N., Obrietan, K. & Chen, G. J. Neurosci. 16, 4283–4292 (1996).

12. Staley, K. J. & Proctor, W. R. J. Physiol. (Lond.)519, 693–712 (1999).

13. Jarolimek, W., Lewen, A. & Misgeld, U. J. Neurosci. 19, 4695–4704 (1999).

reached a higher final state in the cultureswhere GABAA receptor activation wasincreased. Resolving the question of howand why ECl remains 25 mV positive to EKin adult neurons will likely require analyz-ing the expression and post-translationalmodifications of the entire family of neu-ronal chloride transport proteins.

1. Ben-Ari, Y., Cherubini, E., Corradetti, R. &Gaiarsa, J. L. J. Physiol. (Lond.) 416, 303–325(1989).

2. Owens, D. F., Boyce, L. H., Davis, M. B. &Kriegstein, A. R. J. Neurosci. 16, 6414–6423(1996).

3. Ganguly, K., Schinder, A. F., Wong, S. T. &Poo, M. Cell 105, 521–532 (2001).

4. Payne, J. A., Stevenson, T. J. & Donaldson, L. F.

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Fig. 2. GABAA receptor activation is the newest link in the chain of events that change the effect ofGABAA receptor activation from excitation to inhibition. Electroneutral Cl– transport is reversed inadult versus developing neurons because of the increased expression of KCC2 in adults.

A chemokine–glutamateconnectionNicola J. Allen and David Attwell

Chemokine signaling releases glutamate from astrocytes.This process can be amplified by microglia, inducingneurotoxicity, and activated by the HIV coat protein gp120.

The chemokines are a family of chemoat-tractant molecules not normally assumed tohave any connection with fast glutamatergicsignaling in the brain. However, in this issue,Bezzi et al.1 provide evidence for rapidchemokine signaling that triggers glutamate

release. Surprisingly, the glutamate is releasednot from neurons but from astrocytes.Importantly for pathological disorders, thissignaling pathway can lead to neuronal deathby glutamate-evoked apoptosis, and is alsoactivated by the HIV-1 coat protein gp120.This work synthesizes several previously doc-umented mechanisms into one pathway, andhighlights the potential importance of glialglutamate release for both normal andpathological events in the brain.

Chemokine receptors are expressedwidely in neurons and glial cells2, but sig-naling by chemokines is much less wellunderstood than signaling by fast trans-mitters like glutamate. The chemokinestromal-derived factor 1 (SDF-1) seemsto have a role in brain development, inmodulating synaptic transmission and inpathology2. Knocking out SDF-1, or itsG-protein-coupled receptor CXCR4, leadsto premature migration of granule cellsacross the developing cerebellar cortex3,4.SDF-1 is synthesized by astrocytes and toa lesser extent neurons (at least in vitro2),and may alter synaptic transmission, as itevokes a rise of intracellular calcium con-centration in neurons and glia, causes glu-tamate release, and alters spontaneoustransmitter release from neurons5–7. Mostinterestingly, in HIV infection, T-tropicstrains of HIV-1 use CXCR4 as a co-receptor in addition to CD4; the coat pro-tein gp120 binds to CXCR4 and activatesdownstream signaling from this receptor8.

The authors are in the Department ofPhysiology, University College London, Gower Street, London, WC1E 6BT, UK.e-mail: d.attwell@ucl.ac.uk

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