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Modelling the schizophrenic brain
Newsdesk Modelling the schizophrenic brain
208
Maternal viral infections, malnutrition, and stress can precipitate the disease in susceptible people. The link between all three, Jim Koenig (University of Maryland School of Medicine, Baltimore, MD, USA) suggests, is an over-stretched hypothalamic–pituitary–adrenal (HPA) axis. “We know there are abnormalities in the HPA axis in some patients”, he stressed. Koenig has developed a rat model that displays striking similarities with the human disease. Animals that are prenatally stressed display many
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
Shrunken hippocampi in schizophrenia
symptoms of schizophrenia on reaching adulthood such as reduction in working memory, loss of hippoccampal volume, loss of social behaviour, disrupted PPI, and, crucially, the onset of behavioural changes after puberty. “This may be a very valuable heuristic model for learning more about schizophrenia in humans”, enthuses Koenig. One peculiarity of schizophrenia is that symptoms emerge after puberty, with no warning signs. The Lipska animal model—in which neonatal rat pups are injected with the neurotoxin ibotenic acid into the ventral hippocampus on day 7— replicates this peculiar 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) has replicated the Lipska model and found that in adulthood, “these lesioned rats have long-lasting deficits in their capacity to acquire and retain information in spatial and learning tests”, a characteristic also found in people with schizophrenia. Moreau has
Dr Nancy C Andreasen/Science Photo Library
Why are we not all deluded? What keeps us from experiencing the hallucinations that plague people with schizophrenia? These were some of the questions posed at a recent Novartis Foundation meeting (May 27, 2002, London, UK). Apparently, the boundaries of normality can be flimsy: up to 4% of people in Britain have heard a voice in the last year, and as many as 17% of the Dutch population have experienced an isolated delusion. Psychiatrists believe that social interactions anchor our thoughts within the realms of acceptability and compelling evidence from animal models now suggests that isolation may play a critical role in the development of schizophrenia. “It is a deprivation of social play, at a time where it has a crucial effect”, says Trevor Robbins (University of Cambridge, Cambridge, UK). “There is a window of vulnerability in early childhood and early puberty”, he adds. Robbins’ team has seen that rats reared in isolation develop similar cognitive defects to those observed in patients with schizophrenia: their prepulse inhibition (PPI)—a normal inhibition of the startle reflex—drops and their behavioural flexibility is impaired. In addition, Robbins has found alterations in the hippocampus, amygdala, and prefrontal cortex of these rats. That social isolation can exert such a profound impact is at odds with the ‘doomed from the womb’ hypothesis, which views schizophrenia as a purely neurodevelopmental disorder—the result of an early lesion to the hippocampus. Yet the isolation theory rings true with psychiatrists who spend most of their time trying to get their patients with schizophrenia to engage socially. But while the pathophysiology of schizophrenia remains an enigma, most agree the illness is an unfortunate marriage of genetics and the environment. Undoubtedly genes have a major effect, but there is also a strong influence of environmental factors, in particular those affecting the human fetal brain during the second trimester of gestation.
gone one step further and used this model to test antipsychotic drugs. Clozapine, olanzapine, and risperidone reverse the defects in PPI whereas haloperidol does not, a situation that reflects the clinic where some patients only respond to atypical antipsychotics. But how well does this model mimic real life? Of course, people with schizophrenia have not had a hippocampal injection of toxin shortly after birth, but they often have perinatal complications, low birth weight, or hypoxia. “You could imagine that this lesion in the hippocampus [in rats] is crudely modeling what might happen to the hippocampus of a human as a result of some obstetric event causing hypoxia”, says Robin Murray (Institute of Psychiatry, London, UK). The added bonus of looking at animal models is that some rodent strains are more susceptible to environmental triggers than others—a powerful indication that genes deal the deciding hand. Yet opinions remain divided as to how much is attributable to genetics. Murray insists that genes and early environmental insults, separately, are not enough. “Clearly lots of the population are born prematurely or with complications and never develop schizophrenia. However, the effects of such hazards on an individual with genetic predisposition seems to result in aberrant brain circuitry which cannot cope with stresses such as isolation or drug abuse”, he says. Will it ever be possible to model schizophrenia? It is unlikely that researchers will ever know whether a rat hallucinates or a mouse hears alien voices. Schizophrenia is such a complex disorder that, in practice, it may be impossible to mimic all the symptoms in a single animal. Despite the limitations, current models are already providing some new insights. “The animal models are more sophisticated than I had anticipated”, says Murray. “My view used to be that it was too ambitious to model schizophrenia. But I now see that you don’t model schizophrenia but aspects of the syndrome.” Lisa Melton
THE LANCET Neurology Vol 1 August 2002
http://neurology.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
208
Maternal viral infections, malnutrition, and stress can precipitate the disease in susceptible people. The link between all three, Jim Koenig (University of Maryland School of Medicine, Baltimore, MD, USA) suggests, is an over-stretched hypothalamic–pituitary–adrenal (HPA) axis. “We know there are abnormalities in the HPA axis in some patients”, he stressed. Koenig has developed a rat model that displays striking similarities with the human disease. Animals that are prenatally stressed display many
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
Shrunken hippocampi in schizophrenia
symptoms of schizophrenia on reaching adulthood such as reduction in working memory, loss of hippoccampal volume, loss of social behaviour, disrupted PPI, and, crucially, the onset of behavioural changes after puberty. “This may be a very valuable heuristic model for learning more about schizophrenia in humans”, enthuses Koenig. One peculiarity of schizophrenia is that symptoms emerge after puberty, with no warning signs. The Lipska animal model—in which neonatal rat pups are injected with the neurotoxin ibotenic acid into the ventral hippocampus on day 7— replicates this peculiar 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) has replicated the Lipska model and found that in adulthood, “these lesioned rats have long-lasting deficits in their capacity to acquire and retain information in spatial and learning tests”, a characteristic also found in people with schizophrenia. Moreau has
Dr Nancy C Andreasen/Science Photo Library
Why are we not all deluded? What keeps us from experiencing the hallucinations that plague people with schizophrenia? These were some of the questions posed at a recent Novartis Foundation meeting (May 27, 2002, London, UK). Apparently, the boundaries of normality can be flimsy: up to 4% of people in Britain have heard a voice in the last year, and as many as 17% of the Dutch population have experienced an isolated delusion. Psychiatrists believe that social interactions anchor our thoughts within the realms of acceptability and compelling evidence from animal models now suggests that isolation may play a critical role in the development of schizophrenia. “It is a deprivation of social play, at a time where it has a crucial effect”, says Trevor Robbins (University of Cambridge, Cambridge, UK). “There is a window of vulnerability in early childhood and early puberty”, he adds. Robbins’ team has seen that rats reared in isolation develop similar cognitive defects to those observed in patients with schizophrenia: their prepulse inhibition (PPI)—a normal inhibition of the startle reflex—drops and their behavioural flexibility is impaired. In addition, Robbins has found alterations in the hippocampus, amygdala, and prefrontal cortex of these rats. That social isolation can exert such a profound impact is at odds with the ‘doomed from the womb’ hypothesis, which views schizophrenia as a purely neurodevelopmental disorder—the result of an early lesion to the hippocampus. Yet the isolation theory rings true with psychiatrists who spend most of their time trying to get their patients with schizophrenia to engage socially. But while the pathophysiology of schizophrenia remains an enigma, most agree the illness is an unfortunate marriage of genetics and the environment. Undoubtedly genes have a major effect, but there is also a strong influence of environmental factors, in particular those affecting the human fetal brain during the second trimester of gestation.
gone one step further and used this model to test antipsychotic drugs. Clozapine, olanzapine, and risperidone reverse the defects in PPI whereas haloperidol does not, a situation that reflects the clinic where some patients only respond to atypical antipsychotics. But how well does this model mimic real life? Of course, people with schizophrenia have not had a hippocampal injection of toxin shortly after birth, but they often have perinatal complications, low birth weight, or hypoxia. “You could imagine that this lesion in the hippocampus [in rats] is crudely modeling what might happen to the hippocampus of a human as a result of some obstetric event causing hypoxia”, says Robin Murray (Institute of Psychiatry, London, UK). The added bonus of looking at animal models is that some rodent strains are more susceptible to environmental triggers than others—a powerful indication that genes deal the deciding hand. Yet opinions remain divided as to how much is attributable to genetics. Murray insists that genes and early environmental insults, separately, are not enough. “Clearly lots of the population are born prematurely or with complications and never develop schizophrenia. However, the effects of such hazards on an individual with genetic predisposition seems to result in aberrant brain circuitry which cannot cope with stresses such as isolation or drug abuse”, he says. Will it ever be possible to model schizophrenia? It is unlikely that researchers will ever know whether a rat hallucinates or a mouse hears alien voices. Schizophrenia is such a complex disorder that, in practice, it may be impossible to mimic all the symptoms in a single animal. Despite the limitations, current models are already providing some new insights. “The animal models are more sophisticated than I had anticipated”, says Murray. “My view used to be that it was too ambitious to model schizophrenia. But I now see that you don’t model schizophrenia but aspects of the syndrome.” Lisa Melton
THE LANCET Neurology Vol 1 August 2002
http://neurology.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.