The psychobiologu of envrionmental enrichment and "brain reserve" in genetic mouse models of schizophrenia

Anthony Hannan, Emma L. Burrows, Caitlin E. McOmish, Maarten Van Den Buuse

Research output: Contribution to journalMeeting abstractpeer-review


Schizophrenia arises from a complex interplay between genetic and environmental factors. Among the many molecular systems implicated in the
pathogenesis of this brain disorder, various lines of evidence support abnormalities in glutamate signalling, including the schizophreniform psychosis
elicited by NMDA antagonists. Metabotropic glutamate receptor 5 (mGluR5)
has close interactions with NMDA receptors and has been implicated in
endophenotypes of relevance to schizophrenia. The mGluR5 knockout (KO)
mice exhibit reduced prepulse inhibition, locomotor hyperactivity, cognitive
impairment and heightened sensitivity to psychomimetic drugs. These
behavioural abnormalities, together with altered cortical development and
the responsiveness of specific endophenotypes to chronic clozapine administration, support face and predictive validity of these mice as a model
of schizophrenia [1-4]. Environmental enrichment, which enhances levels
of cognitive stimulation and physical activity, has been shown to induce
experience-dependent plasticity and mediate beneficial effects in animal
models of brain disorders, including schizophrenia [5,6]. To investigate
gene-environment interactions within the mGluR5 KO mouse, we housed
mice in standard or environmentally enriched conditions and assessed
their performance in various behavioural tests. We have demonstrated that
enrichment can improve cognition in the Morris water maze and ameliorate
hyperactivity in KO mice. We have previously demonstrated that
KO mice have increased sensitivity to the hyperlocomotive effects of the
psychomimetic MK-801, a NMDA receptor antagonist [3]. Environmentally
enriched and standard housed mice were tested after administration of
varying doses of MK-801. A heightened response was seen in KO mice, with
both low and high doses of MK-801 inducing hyperactivity. Interestingly,
exposure to enrichment exacerbated the MK-801 induced hyperactivity
in KO mice, however had no effect in WT mice. We have additionally
shown that KO mice possess reduced prepulse inhibition and exhibit a
resistance to further reduction due to MK-801 treatment. Enrichment was
shown to reinstate the MK801-induced PPI disruption in KO mice. Our
results demonstrate that behavioural abnormalities relevant to schizophrenia
are selectively ameliorated by environmental enrichment. Furthermore,
they highlight the interactions between mGluR5 and NMDA receptors in
the determination of schizophreniform behaviours. These experimental approaches allow us to model gene-environment interactions in schizophrenia
and explore mechanisms mediating brain and cognitive reserve. This may
also inform the development of “enviromimetics” [7], drugs that mimic
or enhance the beneficial effects of enhanced cognitive stimulation and
physical exercise.

[1] Brody SA, et al. (2004). Mol. Psychiatry 9:35-41.
[2] Brody SA, et al. (2004) Psychopharmacology 172:187-95.
[3] Gray L, et al. (2009) Int. J. Neuropsychopharmacol. 12:45-60.
[4] Hannan AJ (2001) Nature Neurosci. 4:282-8.
[5] Nithianantharajah J, Hannan AJ (2006) Nature Rev. Neurosci. 7:697-709.
[6] McOmish CE, et al. (2007) Mol. Psychiatry 13:661-72.
[7] McOmish CE, Hannan AJ (2007) Expert Opin. Ther. Targets 11:899-913.
Original languageEnglish
Pages (from-to)S12-S12
Number of pages1
JournalSchizophrenia Research
Issue numberSupplement 1
Publication statusPublished - Apr 2012
Externally publishedYes

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