The dual hit hypothesis of schizophrenia: Evidence from animal models

Guerrin, Cyprien G.J.; Doorduin, Janine; Sommer, Iris; Vries, Erik F. J. de

doi:10.1016/j.neubiorev.2021.10.025

Cited by 45 publications

(29 citation statements)

References 190 publications

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“…Imaging studies observed that offspring from rats injected with poly-I:C during pregnancy displayed an altered brain glucose consumption, as measured by [18F]-FDG PET, in the amygdala, hippocampus, and prefrontal cortex [ 15 , 16 ], and higher translocator protein (TSPO) levels in the prefrontal cortex and hippocampus of MIA offspring using [11C]-PK11195 PET, indicative of the presence of neuroinflammation [ 17 ]. The offspring of MIA rats display altered behavioural phenotypes relevant to the positive, cognitive, and negative domains of schizophrenia [ 18 – 22 ]. Notably, studies observed that MIA offspring have impaired prepulse inhibition (PPI), a measure of sensorimotor gating [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

Immune Activation in Pregnant Rats Affects Brain Glucose Consumption, Anxiety-like Behaviour and Recognition Memory in their Male Offspring

et al. 2022

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Purpose Prenatal infection during pregnancy is a risk factor for schizophrenia, as well as for other developmental psychiatric disorders, such as autism and bipolar disorder. Schizophrenia patients were reported to have altered brain metabolism and neuroinflammation. However, the link between prenatal infection, altered brain inflammation and metabolism, and schizophrenia remains unclear. In this project, we aimed to evaluate whether there are changes in brain glucose consumption and microglia activation in the offspring of pregnant rats exposed to maternal immune activation (MIA), and if so, whether these changes occur before or after the initiation of schizophrenia-like behaviour. Procedures Pregnant rats were treated with the viral mimic polyinosinic-polycytidylic acid (MIA group) or saline (control group) on gestational day 15. Static PET scans of the male offspring were acquired on postnatal day (PND) 21, 60, and 90, using [11C]-PK11195 and deoxy-2-[18F]fluoro-D-glucose ([18F]-FDG) as tracers to measure TSPO expression in activated microglia and brain glucose consumption, respectively. On PND60 and PND90, anxiety-like behaviour, recognition memory, and sensorimotor gating were measured using the open field test (OFT), novel object recognition test (NOR), and prepulse inhibition test (PPI). Results [18F]-FDG PET demonstrated that MIA offspring displayed higher brain glucose consumption in the whole brain after weaning (p = 0.017), and in the frontal cortex during late adolescence (p = 0.001) and adulthood (p = 0.037) than control rats. [11C]-PK11195 PET did not reveal any changes in TSPO expression in MIA offspring. Prenatal infection induced age-related behavioural alterations. Adolescent MIA offspring displayed a more anxious state in the OFT than controls (p = 0.042). Adult MIA offspring showed recognition memory deficits in the NOR (p = 0.003). Our study did not show any PPI deficits. Conclusions Our results suggest that prenatal immune activation changed neurodevelopment, resulting in increased brain glucose consumption, but not in microglia activation. The increased brain glucose consumption in the frontal cortex of MIA offspring remained until adulthood and was associated with increased anxiety-like behaviour during adolescence and recognition memory deficits in adulthood.

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Section: Introductionmentioning

confidence: 99%

Immune Activation in Pregnant Rats Affects Brain Glucose Consumption, Anxiety-like Behaviour and Recognition Memory in their Male Offspring

et al. 2022

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“…2 c, 6 a,c, 7 a,c), PPI deficits did not apparently worsen. Guerrin and colleagues ( Guerrin et al, 2021 ) show that first insults can prime/protect against later life adversity. FSL-SIR rats don’t necessarily subscribe to a “dual hit” but rather a gene-X-environment model.…”

Section: Discussionmentioning

confidence: 99%

Bio-behavioural changes in treatment-resistant socially isolated FSL rats show variable or improved response to combined fluoxetine-olanzapine versus olanzapine treatment

Mncube¹,

Harvey²

2022

IBRO Neuroscience Reports

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“…Evidence suggests that the MIA model provides impaired GABAergic transmission at various levels, including changes in GABA receptor expression [ 242 ]. Labouesse et al [ 243 ] showed that prenatal immune activation in mice leads to altered promoter methylation of specific GABAergic genes, Gad1 and Gad2 , in the offspring.…”

Section: Neurodevelopmental Modelsmentioning

confidence: 99%

Advantages and Limitations of Animal Schizophrenia Models

Białoń

Wąsik

2022

IJMS

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Mental illness modeling is still a major challenge for scientists. Animal models of schizophrenia are essential to gain a better understanding of the disease etiopathology and mechanism of action of currently used antipsychotic drugs and help in the search for new and more effective therapies. We can distinguish among pharmacological, genetic, and neurodevelopmental models offering various neuroanatomical disorders and a different spectrum of symptoms of schizophrenia. Modeling schizophrenia is based on inducing damage or changes in the activity of relevant regions in the rodent brain (mainly the prefrontal cortex and hippocampus). Such artificially induced dysfunctions approximately correspond to the lesions found in patients with schizophrenia. However, notably, animal models of mental illness have numerous limitations and never fully reflect the disease state observed in humans.

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The dual hit hypothesis of schizophrenia: Evidence from animal models

Cited by 45 publications

References 190 publications

Immune Activation in Pregnant Rats Affects Brain Glucose Consumption, Anxiety-like Behaviour and Recognition Memory in their Male Offspring

Immune Activation in Pregnant Rats Affects Brain Glucose Consumption, Anxiety-like Behaviour and Recognition Memory in their Male Offspring

Bio-behavioural changes in treatment-resistant socially isolated FSL rats show variable or improved response to combined fluoxetine-olanzapine versus olanzapine treatment

Advantages and Limitations of Animal Schizophrenia Models

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