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THE LANCET Neurology Vol 1 August 2002 http://neurology.thelancet.com208

Why are we not all deluded? Whatkeeps us from experiencing thehallucinations that plague people withschizophrenia? These were some ofthe questions posed at a recentNovartis Foundation meeting (May27, 2002, London, UK). Apparently,the boundaries of normality can beflimsy: up to 4% of people in Britainhave heard a voice in the last year, and as many as 17% of the Dutchpopulation have experienced anisolated delusion. Psychiatrists believethat social interactions anchor ourthoughts within the realms of accept-ability and compelling evidence fromanimal models now suggests thatisolation may play a critical role in thedevelopment of schizophrenia.

“It is a deprivation of social play,at a time where it has a crucial effect”,says Trevor Robbins (University ofCambridge, Cambridge, UK). “Thereis a window of vulnerability in earlychildhood and early puberty”, headds. Robbins’ team has seen that ratsreared in isolation develop similarcognitive defects to those observed inpatients with schizophrenia: theirprepulse inhibition (PPI)—a normalinhibition of the startle reflex—dropsand their behavioural flexibility isimpaired. In addition, Robbins hasfound alterations in the hippocampus,amygdala, and prefrontal cortex ofthese rats.

That social isolation can exert sucha profound impact is at odds with the‘doomed from the womb’ hypothesis,which views schizophrenia as a purelyneurodevelopmental disorder—theresult of an early lesion to thehippocampus. Yet the isolation theoryrings true with psychiatrists whospend most of their time trying to gettheir patients with schizophrenia toengage socially.

But while the pathophysiology ofschizophrenia remains an enigma,most agree the illness is an un-fortunate marriage of genetics and theenvironment. Undoubtedly geneshave a major effect, but there is also astrong influence of environmentalfactors, in particular those affectingthe human fetal brain during thesecond trimester of gestation.

Maternal viral infections, mal-nutrition, and stress can precipitatethe disease in susceptible people. Thelink between all three, Jim Koenig(University of Maryland School ofMedicine, Baltimore, MD, USA)suggests, is an over-stretched hypo-thalamic–pituitary–adrenal (HPA)axis. “We know there are abnor-malities in the HPA axis in somepatients”, he stressed.

Koenig has developed a rat modelthat displays striking similarities withthe human disease. Animals that areprenatally stressed display many

symptoms of schizophrenia onreaching adulthood such as reductionin working memory, loss ofhippoccampal volume, loss of socialbehaviour, disrupted PPI, and,crucially, the onset of behaviouralchanges after puberty. “This may be avery valuable heuristic model forlearning more about schizophrenia inhumans”, enthuses Koenig.

One peculiarity of schizophrenia isthat symptoms emerge after puberty,with no warning signs. The Lipskaanimal model—in which neonatal ratpups are injected with the neurotoxinibotenic acid into the ventralhippocampus on day 7— replicates thispeculiar feature. The timing of this insult corresponds with the end of the second trimester of pregnancy in humans. Jean-Luc Moreau(F Hoffman-La Roche, Switzerland) hasreplicated the Lipska model and foundthat in adulthood, “these lesioned ratshave long-lasting deficits in theircapacity to acquire and retaininformation in spatial and learningtests”, a characteristic also found inpeople with schizophrenia. Moreau has

gone one step further and used thismodel to test antipsychotic drugs.Clozapine, olanzapine, and risperidonereverse the defects in PPI whereashaloperidol does not, a situation thatreflects the clinic where some patientsonly respond to atypical antipsychotics.

But how well does this modelmimic real life? Of course, people withschizophrenia have not had a hippo-campal injection of toxin shortly afterbirth, but they often have perinatalcomplications, low birth weight, orhypoxia. “You could imagine that this lesion in the hippocampus [in rats] is crudely modeling what mighthappen to the hippocampus of ahuman as a result of some obstetricevent causing hypoxia”, says RobinMurray (Institute of Psychiatry,London, UK).

The added bonus of looking atanimal models is that some rodentstrains are more susceptible toenvironmental triggers than others—apowerful indication that genes deal thedeciding hand. Yet opinions remaindivided as to how much is attributableto genetics. Murray insists that genesand early environmental insults,separately, are not enough. “Clearly lotsof the population are born prematurelyor with complications and neverdevelop schizophrenia. However, theeffects of such hazards on an individualwith genetic predisposition seems toresult in aberrant brain circuitry whichcannot cope with stresses such asisolation or drug abuse”, he says.

Will it ever be possible to modelschizophrenia? It is unlikely thatresearchers will ever know whether arat hallucinates or a mouse hears alienvoices. Schizophrenia is such a com-plex disorder that, in practice, it maybe impossible to mimic all thesymptoms in a single animal.

Despite the limitations, currentmodels are already providing somenew insights. “The animal models aremore sophisticated than I hadanticipated”, says Murray. “My viewused to be that it was too ambitious tomodel schizophrenia. But I now seethat you don’t model schizophreniabut aspects of the syndrome.”Lisa Melton

Modelling the schizophrenic brain

Newsdesk

Shrunken hippocampi in schizophrenia

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