Behavioural evaluation of candidate genetic, environmental and developmental murine models for preclinical schizophrenia research
Naert, Arne; M0121009
Valid mouse models of schizophrenia (SCZ) are valuable preclinical research tools to investigate pathogenetic mechanisms and possible treatment strategies for this devastating and poorly understood brain disease. The purpose of current PhD project was to develop and/or evaluate three such models in an extensive test battery that screened for schizophreniform behaviour. The three models focussed on different neurogenetic and environmental factors that have been implicated in SCZ pathogenesis. The first model is a mouse line with haploinsufficiency of the vesicular glutamate transporter 2 (VGLUT2). Behavioural changes of VGLUT2 haploinsufficient mice included hypersensitivity to amphetamine (indirect dopamine agonist) and MK-801 (non-competitive NMDA-receptor antagonist). The second model comprised post-weaning social isolation (isolation rearing) as an environmental manipulation. Such socially isolated mice displayed spontaneous and amphetamine-induced hyperactivity, alterations in prepulse inhibition and habituation of the startle reflex, alterations in social behaviour and impaired extinction of cued fear and spatial memory. In addition, specific brain areas known to be involved in SCZ symptomatology (prefrontal cortex and ventral striatum) showed alterations in gene expression of elements involved in dopamine transmission (dopamine receptor D1 and vesicular monoamine transporter 2). The third model focussed on neurodevelopmental processes involved in SCZ. Lesioning of the ventral hippocampus at neonatal age is known to result in a variety of SCZ-related behaviours in rats, but was here for the first time applied in mice. After anaesthetic procedures as well as lesion coordinates were established in preliminary experiments, behavioural characterization of these mice suggested hyperactivity and alterations in working memory, although large lesion variability comtinued to complicate study results. Experimental results of the three mouse models are discussed in relation to validity of these models as well as their significance in the identification of pathogenetic mechanisms.