The dual hit hypothesis of schizophrenia: Evidence from animal models

Cyprien G.J. Guerrin, Janine Doorduin, Iris E. Sommer, Erik F.J. de Vries
Neuroscience & Biobehavioral Reviews. 2021-12-01; 131: 1150-1168
DOI: 10.1016/j.neubiorev.2021.10.025

Guerrin CGJ(1), Doorduin J(1), Sommer IE(2), de Vries EFJ(3).

Author information:
(1)Department of Nuclear Medicine and Medical Imaging, University of Groningen,
University Medical Centre Groningen, Hanzeplein 1, 9713, GZ, Groningen, the
Netherlands.
(2)Department of Biomedical Sciences of Cells and Systems, University of
Groningen, University Medical Center Groningen, Hanzeplein 1, 9713, GZ,
Groningen, the Netherlands.
(3)Department of Nuclear Medicine and Medical Imaging, University of Groningen,
University Medical Centre Groningen, Hanzeplein 1, 9713, GZ, Groningen, the
Netherlands. Electronic address: .

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.