Differential Effects of MGluR5 Receptor Blockade on Behavior, Schizophrenia-relevant Gene Expression and Neuronal Activation Patterns from Development to Aging Mice

Abstract

Introduction

The glutamate system is implicated both in mood disorders and schizophrenia. Mice lacking metabotropic mGlu5 receptors (mGluR5 KO) display schizophrenia-like abnormalities. Additionally, mGluR5 antagonists represent promising alternative anxiolytics/antidepressants. However, the underlying age-specific molecular/cellular mechanisms are only partially understood.

Objectives

We aimed at identifying molecular alterations associated with a genetically induced mGluR5 deletion, which results in a schizophrenia-like phenotype. Additionally, we investigated age-specific effects of mGluR5 antagonists on emotional behaviour and c-fos activation.

Methods

For analysis of mRNA and protein levels we performed Real-time RT-PCR and Western blot investigations of brains from mGluR5 KO and wild-type mice. Additionally we used classical behavioral tests for determining anxiety- and depression-like changes triggered by the mGluR5 antagonist 2-Methyl-6-(phenylethynyl)pyridine (MPEP). Finally, we used profiling of c-Fos expression, as marker of neuronal activity, induced by MPEP from postnatal day 16 (P16) to adulthood (P90).

Results

We found reduced expression levels of reelin, GAD65, GAD67, parvalbumin, as well as NMDA and AMPA receptor subunits in mGluR5 KO mice, especially in the prefrontal cortex (PFC). We measured age-specific alterations in emotional behaviour of mGluR5 KO mice, with marked increase of anxiety during aging. There was a remarkably conserved activation of the paraventricular nucleus of the hypothalamus, implicated in stress regulation, by MPEP at all investigated ages, whereas the extended amygdala was specifically activated in adulthood only.

Conclusions

Our animal data provide new insights into the potential role of mGluR5 in neurochemical and behavioural changes associated with schizophrenia and mood disorders during the lifespan.

Disclosure of interest

The authors have not supplied their declaration of competing interest.