The 3-hit animal models of schizophrenia: Improving strategy to decipher and treat the disease?

Schizophrenia is a complex disease related to combination and interactions between genetic and environmental factors, with an epigenetic influence. After the development of the first mono-factorial animal models of schizophrenia (1-hit), that reproduced patterns of either positive, negative and/or cognitive symptoms, more complex models combining two factors (2-hit) have been developed to better fit with the multifactorial etiology of the disease. In the two past decades, a new way to design animal models of schizophrenia have emerged by adding a third hit (3-hit). This review aims to discuss the relevance of the risk factors chosen for the tuning of the 3-hit animal models, as well as the validities measurements and their contribution to schizophrenia understanding. We intended to establish a comprehensive overview to help in the choice of factors for the design of multiple-hit animal models of schizophrenia.