1 research outputs found
Persistent gating deficit and increased sensitivity to NMDA receptor antagonism after puberty in a new mouse model of the human 22q11.2 micro-deletion syndrome – a study in male mice
Background: The hemizygous 22q11.2 micro-deletion is a common
copy number variant in humans. The deletion confers high risk
of neurodevelopmental disorders including autism and
schizophrenia. Up to 41% of deletion carriers experience
psychotic symptoms. Methods: We present a new mouse model
(Df(h22q11)/+) of the deletion syndrome (22q11.2DS) and report
on the most comprehensive study undertaken in 22q11.2DS
models. The study was conducted in male mice. Results: We
found elevated post-pubertal NMDA receptor antagonist induced
hyper-locomotion, age-independent prepulse inhibition (PPI)
deficits and increased acoustic startle response (ASR). The
PPI deficit and increased ASR was resistant to antipsychotic
treatment. The PPI deficit was not a consequence of impaired
hearing measured by auditory brain stem responses. The
Df(h22q11)/+ mice also displayed increased amplitude of
loudness-dependent auditory evoked potentials. Prefrontal
cortex and dorsal striatal (DStr) elevations of the dopamine
metabolite DOPAC and increased DStr expression of the AMPA
receptor subunit GluR1 was found. The Df(h22q11)/+ mice did
not deviate from wild-type mice in a wide range of other
behavioural and biochemical assays. Limitations: The 22q11.2
micro-deletion has incomplete penetrance in humans and the
severity of disease depends on the complete genetic makeup in concert with environmental factors. In order to obtain more
marked phenotypes reflecting the severe conditions related to
22q11.2DS it is suggested to expose the Df(h22q11)/+ mice to
environmental stressors which may unmask latent
psychopathology. Conclusion: The Df(h22q11)/+ model will be a
valuable tool for increasing our understanding of the
aetiology of schizophrenia and other psychiatric disorders
associated with the 22q11DS.The research leading to these results was conducted as
part of NEWMEDS and received support from the Innovative
Medicine Initiative Joint Undertaking under grant agreement n°
115008 of which resources are composed of EFPIA in-kind
contribution and financial contribution from the European
Union’s Seventh Framework Programme (FP7/2007-2013). This work
was further supported by grants from the Danish Advanced
Technology Foundation (File no. 001-2009-2) and by the
Instituto de Salud Carlos III, Centro de Investigación
Biomédica en Red de Salud Mental (CIBERSAM)