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 schizophreniarelated behavioral impairments. Furthermore, this role of the mGlu5 receptor is mediated by interaction with NMDA receptor function, which may inform development of novel therapeutics.

Peripubertal exposure to environmental enrichment prevents schizophrenia-like behaviors in the SHR strain animal model

“…In animals, the same increase causes hyperlocomotion, thus, this behavioral alteration has been proposed to model positive symptoms of schizophrenia and is present in SHR and others animal models of this disorder Lipska and Weinberger, 2000;Sams-Dodd et al, 1997;Simpson et al, 2010;van den Buuse et al, 2005). SHRs presented hyperlocomotion and animals of both strains exposed to EE presented a decrease in locomotion.…”

“…Regarding animal models of schizophrenia, EE is a poorly used manipulation. Studies with knockout Phospholipase C-β1 and mGlu5 mice show that EE is able to modulate in a beneficial way some behaviors that mimic schizophrenia symptoms (Burrows et al, 2015;McOmish et al, 2008). Another study, using MK-801 exposure model, show that EE is able to restore PPI deficit in male animals (Nozari et al, 2015).…”

“…In addition, some physiopathological mechanisms are shared by schizophrenia and hypertension, e.g. dopamine dysfunction (Howes and Kapur, 2009;Linthorst et al, 1994;van den Buuse et al, 1991), alterations in the renin-angiotensin system (Campbell et al, 1995;Healy and Printz, 1985;Samani et al, 1989;Wahlbeck et al, 1993Wahlbeck et al, , 1997Wahlbeck et al, , 2000Yongue et al, 1991), nitric oxide dysfunction (Bernstein et al, 2005;Torok, 2008) and oxidative stress (Koga et al, 2015). On the other hand, one methodological weakness intrinsic to this model relates to the fact that control animals does not come from randomizing littermates, as Wistar rats -with genetic and epigenetic differences from SHRs -are used for this purpose.…”

“…Studies have reported that the spontaneously hypertensive rats (SHRs) strain, compared to Wistar normotensive rats, present altered behaviors typically associated to animal models of schizophrenia, such as (I) deficit in contextual fear conditioning (Calzavara et al, 2009) and (II) PPI , both related to cognitive symptoms (Martin et al, 2005;Swerdlow et al, 1994Swerdlow et al, , 2006, (III) impaired social interaction (SI) (Almeida et al, 2013 mimicking the negative symptoms of schizophrenia (O'Tuathaigh et al, 2010;Sams-Dodd, 1995, 1998a, 1998b, 1998cSams-Dodd et al, 1997) and (IV) hyperlocomotion (Almeida et al, 2013Calzavara et al, 2011) that has been proposed to model positive symptoms of schizophrenia (Lipska and Weinberger, 2000;Powell and Miyakawa, 2006;van den Buuse et al, 2005). These alterations are reversed specifically by antipsychotics and potentiated by psychostimulants or other pro-schizophrenia manipulations, showing predictive validity for the model Calzavara et al, 2009;Levin et al, 2011).…”

Decreased expression of mGluR5 within the dorsolateral prefrontal cortex in autism and increased microglial number in mGluR5 knockout mice: Pathophysiological and neurobehavioral implications

“…In addition, mGluR5 knockout (KO) mice also demonstrate hyperlocomotion and deficits in spatial working memory (Burrows et al, 2015;Gray et al, 2009;Jew et al, 2013), together with a lack of novelty-seeking behaviour (Parkitna et al, 2013) and decreased pre-pulse inhibition (Brody et al, 2004;Chen et al, 2010). These findings are of interest given that sensorimotor deficits are seen in individuals with ASD, including excessive movement (De Jong et al, 2011) together with spatial working memory deficits (Steele et al, 2007) and low novelty-seeking behaviours and reward dependence also seen in individuals with ASD (Anckarsater et al, 2006).…”