The dual hit hypothesis of schizophrenia: Evidence from animal models

[Display omitted] •Risk factors for schizophrenia synergistically alter brain function and behaviour.•Single gene mutations have a weak impact on vulnerability to environmental factors.•Maternal immune activation and early maternal separation can increase resilience.•Priming of the immune system may lead to disruption of neurotransmitter systems.•GABAergic, glutamatergic, and dopaminergic systems are involved in susceptibility. 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.