824 | NOVEMBER 2004 | VOLUME 5 www.nature.com/reviews/neuro

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Changes away from the synapse

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According to a study published inthe Journal of Neuroscience, changesto extrasynaptic GABA (γ-aminobutyric acid) receptors in amouse model of epilepsy couldcontribute to overall changes inneural excitability.

Peng et al. studied the expressionof specific GABA receptor subunitsin mice in which epilepsy had beeninduced by treatment withpilocarpine. GABA receptors thatcontain the δ-subunit are usuallyfound outside synapses, where theymight be tonically active oractivated by transmitter spilloverfrom nearby synapses. Theseextrasynaptic GABA receptors arethought to be important forcontrolling neuronal excitability,and mutations in the gene for the δ-subunit have been identified inpatients with generalized epilepsy.

In the mouse model of epilepsythat was used for this study, asingle treatment with pilocarpine

is used to induce a chronicepileptic condition withspontaneous seizures. The authorsmonitored changes in theexpression of the δ-subunit overthe period after the injection. Afterfour days, diffuseimmunohistochemical labellingfor the δ-subunit was decreased inthe molecular layer of the dentategyrus, but after a week this generaldecrease in labelling wasaccompanied by a specific increasein the labelling of interneurons(most of which are inhibitory).These changes were sustained overthe 60 days of the study.

If excitatory neurons in thedentate gyrus have fewerextrasynaptic GABA receptors, andinhibitory interneurons in the samearea have more, this could lead to adecrease in overall inhibition in thisarea and an increase in theexcitability of the neuronalnetwork. To test this, the authors

performed electrophysiology onbrain slices from the pilocarpine-treated mice.As predicted, theseslices were more excitable thanthose from control mice, and theywere also resistant to the normaldecrease in excitability caused bytreatment with a neurosteroid.

These findings point to thepotential importance ofextrasynaptic GABA receptors inepilepsy, and show that differentialchanges in receptor expression ininterneurons and principalneurons might produce acombined effect on excitability inmodels of epilepsy.

Rachel Jones

References and linksORIGINAL RESEARCH PAPER Peng, Z. et al.Altered expression of the δ subunit of theGABAA receptor in a mouse model of temporallobe epilepsy. J. Neurosci. 24, 8629–8639(2004)FURTHER READING Semyanov, A. et al.Tonically active GABAA receptors: modulatinggain and maintaining the tone. TrendsNeurosci. 27, 262–269 (2004)

This splice variant of Cav1.2 is

expressed in many human adult andfetal tissues including the brain, gas-trointestinal system, lungs, immunesystem, smooth muscle and testis — apattern that is consistent with the phe-notypic abnormalities associated withTimothy syndrome. In the brain, it is expressed in regions such as thehippocampus, cerebellum and amyg-dala where abnormalities have beenimplicated in autism.

Splawski and colleagues comparedthe biophysical properties of the wild-type and mutant Ca

v1.2, which were

heterologously expressed in Chinesehamster ovary cells and Xenopus laevisoocytes. The G406R mutation com-pletely abolishes voltage-dependentchannel inactivation of Ca

v1.2 and

results in persistence of inward Ca2+

currents in the cell. Computer simula-tion indicates that a prolonged Ca2+

current in cardiomyocytes mightlengthen cardiac action potentials anddelay repolarization, which would leadto an increased risk of arrhythmia.As the mutant Ca

v1.2 remains sensitive

to calcium channel blockers such as dihydrophyridines, these drugsmight be useful for treating Timothysyndrome and autism.

These findings hint at a potentialmechanism that might underlieautism. Future studies will focus onthe genetic analysis of Ca

v1.2 and

other calcium channels in the disorderand the potential application ofcalcium channel blocker therapy.

Jane QiuReferences and links

ORIGINAL RESEARCH PAPER Splawski, I. et al.Cav1.2 calcium channel dysfunction causes amultisystem disorder including arrhythmia andautism. Cell 119, 19–31 (2004)FURTHER READING Zoghbi, H.Y. Postnatalneurodevelopmental disorders: meeting at thesynpase? Science 302, 826–830 (2003)

Autism affects 0.5% of childrenaround the world and causes great dis-tress, but little is known about themolecular mechanisms involved inthis disorder and no therapy is yetavailable. Reporting in Cell, Splawskiand colleagues implicate abnormalcalcium signalling in autism, andhighlight the therapeutic potential ofcalcium channel blockers.

The authors characterized thephenotypes and molecular basis of Timothy syndrome — a novel disorder that is associated with condi-tions in multiple organ systems,including lethal arrhythmias, immunedeficiency and autism. They dis-covered a de novo missense mutationin a splice variant of the calcium L-type channel, Ca

v1.2, in 13 patients

with the syndrome. The mutation,G406R, caused a substitution ofglycine with arginine at residue 406.

Making sense of smellNeuroscience is already wellrepresented in the list of NobelPrize laureates, and it wasrecently announced that the2004 prize for physiology ormedicine has been awardedto Linda Buck and RichardAxel for unlocking the secretsof what the Nobel Assemblydescribed as “the mostenigmatic of our senses” —the sense of smell.

Buck was a seniorpostdoctoral fellow in Axel’slaboratory in 1991 when thepair published their seminalpaper on the discovery of afamily of around 1,000‘odorant receptor’ genes.They subsequently becamecompetitors in the race toestablish how thesereceptors are deployed in thedetection of over 10,000different odours — aresearch effort that gave riseto the concept of acombinatorial olfactory code,which was described by Axelas “the brain…essentiallysaying something like ‘I’mseeing activity in positions 1,15, and 54 of the olfactorybulb, which corresponds toodorant receptors 1, 15, and54, so that must be jasmine’”(Times Online, UK, 4October).

As well as exposing theworkings of the olfactorysystem, this research hascontributed substantially toour understanding of the linkbetween olfaction andmemory: “how very specificsmells — a great red wine,the scent of a lover or even anunfresh clam — can remainembedded in the humanbrain for years, only to betriggered half a lifetime laterby a similar smell” (TimesOnline). This phenomenonwas famously illustrated in“Marcel Proust’s novelRemembrance of ThingsPast, where the smell andtaste of a single madeleinecake triggers a long string ofmemories” (DiscoveryChannel, USA, 4 October).

When asked what heplanned to do next, Axelsaid: “I’m going to have acup of coffee” (New YorkTimes, 4 October).

Heather Wood

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