title: Environmental Enrichment Ameliorates Behavioral Impairments Modeling Schizophrenia in Mice Lacking Metabotropic Glutamate Receptor 5.
abstract: Schizophrenia arises from a complex interplay between genetic and environmental factors. Abnormalities in glutamatergic signaling have been proposed to underlie the emergence of symptoms, in light of various lines of evidence, including the psychotomimetic effects of NMDA receptor antagonists. Metabotropic glutamate receptor 5 (mGlu5) has also been implicated in the disorder, and has been shown to physically interact with NMDA receptors. To clarify the role of mGlu5-dependent behavioral expression by environmental factors, we assessed mGlu5 knockout (KO) mice after exposure to environmental enrichment (EE) or reared under standard conditions. The mGlu5 KO mice showed reduced prepulse inhibition (PPI), long-term memory deficits, and spontaneous locomotor hyperactivity, which were all attenuated by EE. Examining the cellular impact of genetic and environmental manipulation, we show that EE significantly increased pyramidal cell dendritic branching and BDNF protein levels in the hippocampus of wild-type mice; however, mGlu5 KO mice were resistant to these alterations, suggesting that mGlu5 is critical to these responses. A selective effect of EE on the behavioral response to the NMDA receptor antagonist MK-801 in mGlu5 KO mice was seen. MK-801-induced hyperlocomotion was further potentiated in enriched mGlu5 KO mice and treatment with MK-801 reinstated PPI disruption in EE mGlu5 KO mice only, a response that is absent under standard housing conditions. Together, these results demonstrate an important role for mGlu5 in environmental modulation of schizophrenia-related behavioral impairments. Furthermore, this role of the mGlu5 receptor is mediated by interaction with NMDA receptor function, which may inform development of novel therapeutics.
authors: Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, VIC, Australia.
authors: Emma L
authors: EL
authors: Burrows
authors: 1] Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, VIC, Australia [2] Department of Psychiatry, The Sackler Institute for Developmental Psychobiology, Columbia University, NY, USA.
authors: Caitlin E
authors: CE
authors: McOmish
authors: 1] Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, VIC, Australia [2] School of Psychological Science, La Trobe University, Bundoora, VIC, Australia.
authors: Laetitia S
authors: LS
authors: Buret
authors: 1] Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, VIC, Australia [2] School of Psychological Science, La Trobe University, Bundoora, VIC, Australia.
authors: Maarten
authors: M
authors: Van den Buuse
authors: 1] Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, VIC, Australia [2] Department of Anatomy and Neuroscience, University of Melbourne, Parkville, VIC, Australia.
authors: Anthony J
authors: 0000000175328922
authors: AJ
authors: Hannan
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003623:Dark Adaptation / Q000235:genetics; D003712:Dendrites / Q000473:pathology; D004195:Disease Models, Animal; D004777:Environment; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000209:etiology / Q000628:therapy; D001523:Mental Disorders / Q000209:etiology* / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D065808:Prepulse Inhibition / Q000235:genetics; D017966:Pyramidal Cells / Q000473:pathology; D064529:Receptor, Metabotropic Glutamate 5 / Q000172:deficiency* / Q000235:genetics; D012559:Schizophrenia / Q000150:complications* / Q000235:genetics* / Q000473:pathology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D064529:Receptor, Metabotropic Glutamate 5