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THE LANCET Neurology Vol 1 October 2002 http://neurology.thelancet.com336

Newsdesk

Caffeine has its stimulant effect byacting as an antagonist at adenosineA2A receptors. Now, new research hasshown that the mechanism mediatingthis effect is dependent on anintracellular protein—dopamine andcyclic AMP-regulated phosphoproteinof relative molecular mass 32 000(DARPP-32). “We have now foundthat the stimulant action of caffeine involves phosphorylation ofDARPP-32, a protein highlyconcentrated in the basal ganglia”,explains Gilberto Fisone (KarolinskaInstitutet, Stockholm, Sweden), one ofthe researchers. Caffeine stimulatesmotor activity by damping downcertain inhibitory pathways in thebasal ganglia.

Fisone and co-workers useddouble in situ hybridisation todemonstrate the expression of A2A

receptors in about half of the DARPP-32-containing neurons in the mouse

striatum. They then investigated theeffects of caffeine and other A2A

antagonists and agonists in wild-typemice and in knockout mice lackingthe DARPP-32 protein. Theymeasured the motor response of miceto these compounds, and determinedwhich intracellular signalling path-ways were activated (Nature 2002;418: 774–78).

In wild-type mice, caffeine(7·5mg/kg) caused an increase inlocomotor activity and motility—aneffect that was significantly reduced inmice lacking the DARPP-32 protein.The researchers observed a similarresponse with the A2A antagonistSCH-58261 and exactly the oppositeeffect with the A2A agonist CGS-21680.

By use of antibody bindingdetected by chemiluminescence,Fisone and colleagues identified anincrease in phosphorylation ofDARPP-32 at the threonine 75

(Thr75) residue after administrationof caffeine or SCH-58261. Thisincrease in phosphorylation could becaused either by increased activity ofCdk5 (an enzyme that phosphorylatesat Thr75) or to inhibition of proteinphosphatase-2A (PP-2A; an enzymethat dephosphorylates at Thr75).Further study with inhibitors of thesetwo proteins revealed that the increaseof Thr75 phosphorylation is due toinhibition of PP-2A.

In an accompanying commentary,Jean-Marie Vaugois (Universite deRouen, France) writes “future effortswill identify the target proteins that areregulated by this signalling cascade”.

Fisone concludes, “besides provid-ing a molecular explanation for theaction of caffeine, which is the mostused stimulant in the world, ourresults help to better understand thefunctioning of the basal ganglia”.Rebecca Love

Caffeine-stimulated research—DARPP-32 and the basal ganglia

Palau, a remote island in the SouthPacific, is the focus of a new study toinvestigate the genetic basis ofschizophrenia. A team of researchersfrom the Universities of California(Irvine, USA) and Pittsburgh (PA,USA) and Palau itself have analysed thegenome of members of five islandfamilies, many of whom are affected bythe disease. Their results show thatregions of chromosomes 5, 3, and 9warrant further investigation.

William Byerley and colleaguesperformed genome screening on 40 ofthe island’s 155 patients withschizophrenia. Family links wererecorded from genealogical informationgiven by multiple family members andverified with 400 genetic markers. Inone family, 7 of 9 people withschizophrenia shared a strong linkagesignal indicating the presence ofsusceptibility loci on chromosome 5q.This region seems to be unique as it isdistal to a previously identifiedsusceptibility region on thischromosome. A weaker signal, in adifferent region on chromosome 5q,occurred in a second family. Regions on

chromosome 9p, and on chromosome3q in particular, also look promising.(Mol Psychiatry 2002; 7: 689–94).

“As none of the families exhibit the same signals, the origins of schizo-phrenia in the Palau population appear

to be heterogeneous”, commentsByerley. Douglas Blackwood (Edin-burgh University, UK) welcomes thestudy as a valuable contribution to theefforts to pinpoint the genes underlyingschizophrenia. “So far, no gene has beenunequivocally linked to the disease, butas soon as we have a firm link, thisshould identify a molecular pathway inthe neuron that can be investigatedfurther. It is likely that many genes are

involved in one or more such pathwaysand eventually this approach shouldhome in on the molecular basis of thedisease and should also suggest newtherapeutic targets”, he comments.

David Curtis (St Bartholomew’sand Royal London School of Medicineand Dentistry, London, UK) points outthat other research groups have alreadyproposed candidate genes and says thatexciting developments are expected atthe World Congress on PsychiatricGenetics in Brussels on October 10,2002. “Two or three potentialschizophrenia and bipolar disordersusceptibility genes look particularlyinteresting”, adds Curtis. Byerley’sgroup now plans to use informationfrom the human genome sequence tolook for mutations in candidate genesin the regions of linkage identified onPalau. “We will soon finish genome-wide surveys using all affected Palaufamilies and all Palau schizophrenics—the first time that a completepopulation of schizophrenics will havebeen analysed: hopefully more clues willemerge”, he says.Kathryn Senior

Isolated island population studied in hunt for schizophrenia genes

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