Title: Behavioural evaluation of candidate genetic, environmental and developmental murine models for preclinical schizophrenia research
Authors: Naert, Arne; M0121009
Issue Date: 6-Jun-2011
Abstract: 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.
Publication status: published
KU Leuven publication type: TH
Appears in Collections:Laboratory for Biological Psychology

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