Modeling the positive symptoms of schizophrenia in genetically modified mice: pharmacology and methodology aspects

Abstract

In recent years, there have been huge advances in the use of genetically modified mice to study pathophysiological mechanisms involved in schizophrenia. This has allowed rapid progress in our understanding of the role of several proposed gene mechanisms in schizophrenia, and yet this research has also revealed how much still remains unresolved. Behavioral studies in genetically modified mice are reviewed with special emphasis on modeling psychotic-like behavior. I will particularly focus on observations on locomotor hyperactivity and disruptions of prepulse inhibition (PPI). Recommendations are included to address pharmacological and methodological aspects in future studies. Mouse models of dopaminergic and glutamatergic dysfunction are then discussed, reflecting the most important and widely studied neurotransmitter systems in schizophrenia. Subsequently, psychosis-like behavior in mice with modifications in the most widely studied schizophrenia susceptibility genes is reviewed. Taken together, the available studies reveal a wealth of available data which have already provided crucial new insight and mechanistic clues which could lead to new treatments or even prevention strategies for schizophrenia.

Fig. 1.

The Effect of Different Doses of Amphetamine (amph, Top Panel) and MK-801 (MK, Bottom Panel) on Locomotor Activity of C57BL/6 Mice (M. van den Buuse, unpublished data). Both drugs showed little effect at the lowest dose, markedly increase locomotor distance moved at the middle dose, but induced low scores at the highest dose, presumably because of the induction of stereotyped responses which disrupted ambulatory activity. Depending on the dose of the drug, an increase of locomotor distance moved displayed by a genetically modified mouse model could either mean hypersensitivity or hyposensitivity to the treatment. Locomotor distance moved was assessed using automated photocell cages (see van den Buuse et al for details). Doses indicated are in milligram per kilogram. There were 8–20 mice per group, and data are expressed as mean ± standard error of the mean.

Fig. 2.

Comparison of PPI of C57BL/6 and 129Sv Mice (M. van den Buuse, unpublished data). Startle amplitude was much greater in 129Sv mice than in C57BL/6 although startle habituation was not different (panel A). PPI tended to be higher in 129Sv mice than in C57BL/6 at both the 30-ms ISI (panel B) or 100 ms ISI (panel C). There were differential as well as similar effects between the strains, depending on the parameter measured and drug tested. Genetic modifications on either a C57BL/6 or 129Sv genetic background may have profoundly different effects on these baseline levels. Experiments included the effect of 5 mg/kg of apomorphine, 5 mg/kg of amphetamine, and 0.25 mg/kg of MK-801 on average startle (panel D), PPI at the 30-ms ISI (panel E), and PPI at the 100-ms ISI (panel E). For methodological details, see van den Buuse et al., Data are expressed as mean ± SEM of n = 8–12. *P < .05 compared with the saline condition in the same strain (analyzed by analysis of variance).