Metabotropic Glutamate Receptor Subtype 7 Ablation Causes Dysregulation of the HPA Axis and Increases Hippocampal BDNF Protein Levels: Implications for Stress-Related Psychiatric Disorders

Abstract

Regulation of neurotransmission via group-III metabotropic glutamate receptors (mGluR4, -6, -7, and -8) has recently been implicated in the pathophysiology of affective disorders, such as major depression and anxiety. For instance, mice with a targeted deletion of the gene for mGluR7 (mGluR7 À/À ) showed antidepressant and anxiolytic-like effects in a variety of stress-related paradigms, including the forced swim stress and the stress-induced hyperthermia tests. Deletion of mGluR7 reduces also amygdala-and hippocampus-dependent conditioned fear and aversion responses. Since the hypothalamic-pituitary-adrenal (HPA) axis regulates the stress response we investigate whether parameters of the HPA axis at the levels of selected mRNA transcripts and endocrine hormones are altered in mGluR7-deficient mice. Over all, mGluR7 À/À mice showed only moderately lower serum levels of corticosterone and ACTH compared with mGluR7 + / + mice. More strikingly however, we found strong evidence for upregulated glucocorticoid receptor (GR)-dependent feedback suppression of the HPA axis in mice with mGluR7 deficiency: (i) mRNA transcripts of GR were significantly upregulated in the hippocampus of mGluR7 À/À animals, (ii) similar increases were seen with 5-HT 1A receptor transcripts, which are thought to be directly controlled by the transcription factor GR and finally (iii) mGluR7 À/À mice showed elevated sensitivity to dexamethasone-induced suppression of serum corticosterone when compared with mGluR7 + / + animals. These results indicate that mGluR7 deficiency causes dysregulation of HPA axis parameters, which may account, at least in part, for the phenotype of mGluR7 À/À mice in animal models for anxiety and depression. In addition, we present evidence that protein levels of brain-derived neurotrophic factor are also elevated in the hippocampus of mGluR7 À/À mice, which we discuss in the context of the antidepressant-like phenotype found in those animals. We conclude that genetic ablation of mGluR7 in mice interferes at multiple sites in the neuronal circuitry and molecular pathways implicated in affective disorders.

Genetic Strain Differences in Learned Fear Inhibition Associated with Variation in Neuroendocrine, Autonomic, and Amygdala Dendritic Phenotypes

“…Blood samples were taken 6 h later (1700-1800 hours). Doses were based on those previously described for mice on a C57BL/6 background (Mitsukawa et al, 2006;Ridder et al, 2005). The effects of strain and treatment were analyzed using two-factor ANOVA and Newman-Keuls post hoc tests.…”

mGluR7 facilitates extinction of aversive memories and controls amygdala plasticity

“…37 We have validated a method for siRNA-induced knockdown in the mouse. 16 As many of the initial studies of mGluR7 have relied on information from mGluR7 knockout animals, 10,12,38,39 which are bred on a C57BL/6 background, we chose to conduct our siRNA studies on this background. Seventy-four male C57BL/6 mice (23-31 g; Charles River, France) were housed and surgeries performed as described previously, 15 40 ).…”

Viral-Mediated Knockdown of mGluR7 in the Nucleus Accumbens Mediates Excessive Alcohol Drinking and Increased Ethanol-Elicited Conditioned Place Preference in Rats

“…As such, dysregulation of mGluR7 has been linked to many psychiatric diseases including depression (Bradley et al, 2011;Cryan et al, 2003), anxiety (Fendt et al, 2008;Mitsukawa et al, 2006), schizophrenia (Bolonna et al, 2001;Ohtsuki et al, 2008) and drug addiction Li et al, 2009Li et al, , 2010. In rodents, results have indicated that the mGluR7 allosteric agonist N,N'-dibenzyhydryl-ethane-1,2-diamine dihydrochloride (AMN082) dose dependently inhibits cocaine-induced enhancement of electrical brainstimulation reward and intravenous cocaine self-administration in rats ).…”