© 2001 Macmillan Magazines Ltd

Lasting changes in the strength ofglutamate synapses — long-termpotentiation (LTP) or depression(LTD) — occur following activity-dependent changes in calciumconcentration in the postsynapticneuron. Paradoxically, both LTPand LTD seem to depend onincreases in intracellular calcium.This has led to the proposal that thedirection of the change in synapticstrength is determined by the size ofthe increase in postsynaptic calciumconcentration, with progressivelyhigher calcium causing first LTDand then LTP.

Cho et al. tested this theory in ratperirhinal cortex by using differentconcentrations of EGTA to bufferactivity-dependent increases inpostsynaptic calcium to differentdegrees. They found thatstimulation that would normally

cause LTP induced LTD instead if ahigh concentration of EGTA waspresent to limit the rise in calciumconcentration.

Interestingly, they also found thatmoderate levels of the buffer wouldprevent both LTP and LTD. Thereseems to be a ‘neutral zone’, betweenconcentrations of calcium thatwould normally induce LTD andthose that would normally induceLTP, where neither takes place. Thisis reminiscent of the Bienenstock–Cooper– Munro (BCM) model,which proposes that low frequenciesof stimulation will cause LTD,moderate frequencies will cause nochange in synaptic strength, andhigh frequencies will cause LTP.

Is the lack of plasticity in thisneutral zone the result of LTD andLTP balancing each other out, or arethey both absent? Cho et al. testedthis by selectively blocking LTD(using the mGlu receptor antagonistMCPG) or LTP (using the proteinkinase inhibitor staurosporine) andrepeating the experiment.When

activity-dependent calcium levelswere buffered to the neutral zonelevels and LTD was blocked, LTP stilldid not occur; likewise, blocking LTPunder similar levels of calciumbuffering failed to uncover LTD.

So it seems that the cessation ofLTD as calcium levels rise from lowto moderate is independent of theinduction of LTP at still higherlevels. This raises the possibility thatthe higher calcium levels required toinduce LTP actually inhibit themechanisms of induction of LTD.Although the full picture of themolecular mechanisms underlyinglong-term plasticity is far from clear,these data provide anotherimportant piece of the jigsaw.

Rachel Jones

References and linksORIGINAL RESEARCH PAPER Cho, K. et al.An experimental test of the role ofpostsynaptic calcium levels in determiningsynaptic strength using perirhinal cortex of rat.J. Physiol. 532, 459–466 (2001) FURTHER READING Malenka, R. C. & Nicoll,R. A. Long-term potentiation — a decade ofprogress? Science 285, 1870–1874 (1999)

380 | JUNE 2001 | VOLUME 2 www.nature.com/reviews/neuro

H I G H L I G H T S

Highs and lows

S Y N A P T I C P L A S T I C I T Y

AChBP has sig-nificant sequencehomology to ligand-gated ion-channels (LGICs). In par-ticular, AChBP resembles the ligand-binding site of nicotinic AChreceptors. In a companion paper,Brejc et al. report that they have solvedthe crystal structure of AChBP and,indirectly, gained new insights into thestructure of the ACh-receptor bindingsite.As predicted for the ACh receptor,AChBP forms pentamers in which thebinding site is at the interface betweensubunits. The authors identified theresidues that form the binding siteand noted that they vary amongLGICs, reflecting perhaps their differ-ent binding properties. By contrast,residues conserved between AChBPand LGICs do not contribute to thebinding site but seem to stabilize theglobal structure of each subunit.

So, in addition to re-emphasizingthe influence of glial cells on synaptic

transmission, the study of AChBPconstitutes a double triumph, pro-viding the first detailed three-dimen-sional account of the ACh bindingsite. This crystallographic analysiswill have a great influence on struc-tural studies of other LGICs, com-parable only to the impact that thestructure of KcsA has had on thestudy of other voltage-gated ionchannels.

Juan Carlos López

References and linksORIGINAL RESEARCH PAPER Smit, A. B. et al.A glia-derived acetylcholine-binding protein thatmodulates synaptic transmission. Nature 411,261–268 (2001) | Brejc, K. et al. Crystal structureof an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors. Nature 411,269–276 (2001) FURTHER READING Haydon, P. G. Glia: listeningand talking to the synapse. Nature Rev. Neurosci.2, 185–193 (2001) | Corringer, P. J. et al. Nicotinicreceptors at the amino-acid level. Annu. Rev.Pharmacol. Toxicol. 40, 431–458 (2000)

The profound effect that glial cellshave on neurotransmission continuesto gain notoriety; hardly a monthpasses without an important break-through in this flourishing field. Thelatest development has come fromthe study of acetylcholine (ACh)-mediated transmission in the snailLymnaea stagnalis. In this system,Smit et al. have identified an ACh-binding protein (AChBP) released byglia, which can directly modulate theefficacy of synaptic transmission.

The authors observed that if apresynaptic neuron was stimulatedrepeatedly, the presence of a glial cellaround the synapse caused a reductionin the postsynaptic, ACh-dependentresponse. By analysing this modula-tion in detail, Smit et al. determinedthat the glial cell responded to AChand released AChBP, which thenacted as a molecular decoy, bindingthe transmitter and reducing itsavailability at the synapse.

Death is not the endAnother day, another stemcell story, or so it seems.“Brain cells of corpses aregrown in test tube”,announces The Independent(UK, 3 May 2001),responding to the news thatFred Gage’s research teamat the Salk Institute haveshown that neuralprogenitor cells can bepropagated from adulthuman cadaver brains(Nature, 3 May 2001).

Their finding is importantbecause it might provide analternative to thecontroversial practice ofderiving stem cells fromembryonic tissue. However,as Peter Andrews, a stem-cell researcher from theUniversity of Sheffield, pointsout, “the use of cadavers asa potential source of stemcells raises a different set ofethical issues to thoseassociated with using stemcells from embryos” (BBCNews Online, 2 May 2001),and Gage’s team admit that“complex ethical andsocietal issues” (Nature, 3May 2001) need to beaddressed.

Some reports also raiseconcerns that, with all thehype surrounding stem-cellresearch, we might be losingsight of the science. Writingfor BBC News Online (2 May2001), Helen Briggssuggests that “research hasbeen overshadowed byethical objections about thesource of the tissue”. PeterGorner in the ChicagoTribune (3 May 2001) saysthat “[Gage] is worried thatthe public has become soinundated by stories aboutembryonic stem cells …that the science thatunderlies the ethical debateoften gets short shrift”. In thesame article, Gage is quotedas saying “We haven’tproved that these are stemcells. They’re what areknown as progenitor cells…stem cells also have theability to reproducethemselves and keep ondividing indefinitely, and wehaven’t yet shown that thesecells will do that”.

Heather Wood

IN THE NEWS

Crystal-clear glia–neuroninteractions

G L I A

AChvAChTChAT

High-affinitycholine uptake

Na+

Presynaptic neuron

Postsynaptic site

Choline

Choline

ACh

NeuronalAChR

AChE

Glial AChR

Glialcell

AChBP

Na+