The dual hit hypothesis of schizophrenia:evidence from animal models

Schizophrenia is a heterogeneous psychiatric disorder, which can severely impact social and professional functioning. Epidemiological and clinical studies show that schizophrenia has a multifactorial aetiology comprising genetic and environmental risk factors. Although several risk factors have been identified, it is still not clear how they result in schizophrenia. This knowledge gap, however, can be investigated in animal studies. In this review, we summarise animal studies regarding molecular and cellular mechanisms through which genetic and environmental factors may affect brain development, ultimately causing schizophrenia. Preclinical studies suggest that early environmental risk factors can affect the immune, GABAergic, glutamatergic, or dopaminergic system and thus increase the susceptibility to another risk factor later in life. A second insult, like social isolation, stress, or drug abuse, can further disrupt these systems and the interactions between them, leading to behavioural abnormalities. Surprisingly, first insults like maternal infection and early maternal separation can also have protective effects. Single gene mutations associated with schizophrenia did not have a major impact on the susceptibility to subsequent environmental hits

Maternal infection during pregnancy aggravates the behavioral response to an immune challenge during adolescence in female rats

Prenatal and early postnatal infection have been associated with changes in microglial activity and the development of psychiatric disorders. Here, we investigated the effect of prenatal immune activation and postnatal immune challenge, alone and combined, on behavior and microglial cell density in female Wistar rats. Pregnant rats were injected with poly I:C to induce a maternal immune activation (MIA). Their female offspring were subsequently exposed to a lipopolysaccharide (LPS) immune challenge during adolescence. Anhedonia, social behavior, anxiety, locomotion, and working memory were measured with the sucrose preference, social interaction, open field, elevated-plus maze, and Y-maze test, respectively. Microglia cell density was quantified by counting the number of Iba-1 positive cells in the brain cortex. Female MIA offspring were more susceptible to the LPS immune challenge during adolescence than control offspring as demonstrated by a more pronounced reduction in sucrose preference and body weight on the days following the LPS immune challenge. Furthermore, only the rats exposed to both MIA and LPS showed long-lasting changes in social behavior and locomotion. Conversely, the combination MIA and LPS prevented the anxiety induced by MIA alone during adulthood. MIA, LPS, or their combination did not change microglial cell density in the parietal and frontal cortex of adult rats. The results of our study suggest that the maternal immune activation during pregnancy aggravates the response to an immune challenge during adolescence in female rats.</p

A single dose of ketamine cannot prevent protracted stress-induced anhedonia and neuroinflammation in rats

Worldwide, millions of people suffer from treatment-resistant depression. Ketamine, a glutamatergic receptor antagonist, can have a rapid antidepressant effect even in treatment-resistant patients. A proposed mechanism for the antidepressant effect of ketamine is the reduction of neuroinflammation. To further explore this hypothesis, we investigated whether a single dose of ketamine can modulate protracted neuroinflammation in a repeated social defeat (RSD) stress rat model, which resembles features of depression. To this end, male animals exposed to RSD were injected with ketamine (20 mg/kg) or vehicle. A combination of behavioral analyses and PET scans of the inflammatory marker TSPO in the brain were performed. Rats submitted to RSD showed anhedonia-like behavior in the sucrose preference test, decreased weight gain, and increased TSPO levels in the insular and entorhinal cortices, as observed by [11C]-PK11195 PET. Whole brain TSPO levels correlated with corticosterone levels in several brain regions of RSD exposed animals, but not in controls. Ketamine injection 1 day after RSD disrupted the correlation between TSPO levels and serum corticosterone levels, but had no effect on depressive-like symptoms, weight gain or the protracted RSD-induced increase in TSPO expression in male rats. These results suggest that ketamine does not exert its effect on the hypothalamic-pituitary-adrenal axis by modulation of neuroinflammation

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

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

The dual hit hypothesis of schizophrenia: evidence from animal models

Schizophrenia is a heterogeneous psychiatric disorder, which can severely impact social and professional functioning. Epidemiological and clinical studies show that schizophrenia has a multifactorial aetiology comprising genetic and environmental risk factors. Although several risk factors have been identified, it is still not clear how they result in schizophrenia. This knowledge gap, however, can be investigated in animal studies. In this review, we summarise animal studies regarding molecular and cellular mechanisms through which genetic and environmental factors may affect brain development, ultimately causing schizophrenia. Preclinical studies suggest that early environmental risk factors can affect the immune, GABAergic, glutamatergic, or dopaminergic system and thus increase the susceptibility to another risk factor later in life. A second insult, like social isolation, stress, or drug abuse, can further disrupt these systems and the interactions between them, leading to behavioural abnormalities. Surprisingly, first insults like maternal infection and early maternal separation can also have protective effects. Single gene mutations associated with schizophrenia did not have a major impact on the susceptibility to subsequent environmental hits

Social adversity during juvenile age but not adulthood increases susceptibility to an immune challenge later in life

Adverse experiences in early life can increase mental vulnerability to immune challenges experienced later in life, which may induce the development of stress-related psychopathologies. Here, we investigated whether the combined effect of both events is higher if the first adverse experience occurs when the brain is still in development. Therefore, male Wistar rats were exposed to repeated social defeat (RSD, first hit) during juvenile age or adulthood and to an immune challenge consisting of a single injection of lipopolysaccharide (LPS, second hit) in adulthood. Control animals were not exposed to RSD, but only to the LPS challenge. Translocator protein density, a marker for reactive microglia, microglia cell density and plasma corticosterone levels were measured using in vivo [ 11C]PBR28 positron emission tomography, iba1 immunostaining, and corticosterone ELISA, respectively. Anhedonia, social behavior and anxiety were measured with the sucrose preference, social interaction, and open field tests, respectively. Rats exposed to RSD during juvenile age exhibited enhanced anhedonia and social interaction dysfunction after an immune challenge in adulthood. This enhanced susceptibility was not observed in rats exposed to RSD during adulthood. In addition, exposure to RSD synergistically increased microglia cell density and glial reactivity to the LPS challenge. This increase in microglia cell density and reactivity to the LPS challenge was more pronounced in rats exposed to RSD during juvenile age than in adulthood. Exposure to RSD alone in juvenile age or adulthood induced similar short-term anhedonia, a long-lasting increase in plasma corticosterone and microglial activity, but no change in anxiety and social behavior. Our findings indicate that exposure to social stress during juvenile age, but not adulthood, primes the immune system and increases the sensitivity to an immune challenge experienced later in life. This suggests that juvenile social stress can have more deleterious effects in the long term than similar stress in adulthood