Allosteric activation and genetic antagonism of metabotropic glutamate receptor subtype 7 (mGluR7) : implications for stress-related physiology and behavior

Metabotropic glutamate receptor subtypes (mGluR1 to -8) act as pre- and postsynaptic regulators of neurotransmission in the central nervous system. Regulation of neurotransmission via metabotropic glutamate receptors has recently been implicated in the pathophysiology of anxiety and stress-related disorders including depression. Among metabotropic glutamate receptor subtypes, the group III metabotropic glutamate receptor subtype 7 (mGluR7) shows the highest evolutionary conservation (Flor et al., 1997; Makoff et al., 1996), which suggests that this receptor could play an important physiological role. Cryan et al. (2003) have demonstrated that mice with a targeted deletion of the gene for mGluR7 (mGluR7-/-) show antidepressant and anxiolytic-like effects in a variety of stress-related paradigms, including the forced swim stress and the stress-induced hyperthermia tests. Furthermore, the same group has recently developed mGluR7 knockdown using siRNA, which further supported the critical role of mGluR7 in anxiety- and stress-related behaviors (Thakker et al., 2005). Since the hypothalamic-pituitary-adrenal (HPA) axis regulates stress responses, it was investigated in this thesis whether the levels of selected mRNA transcripts and endocrine hormones were altered in mGluR7 deficient mice in the HPA axis. Over all, mGluR7-/- mice showed only moderately lower serum levels of corticosterone and adrenocorticotropic hormone (ACTH) compared to mGluR7+/+ mice. However, strong evidence has been found for up-regulation of glucocorticoid receptor (GR)-dependent feedback suppression of the HPA axis in mice with mGluR7 deficiency: (i) mRNA transcripts of GR were significantly higher in the hippocampus of mGluR7-/- animals, (ii) similar increases were seen for 5-HT1A receptor transcripts which are thought to be directly controlled by the GR transcription factor and finally (iii) mGluR7-/- 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-/- mice in animal models for anxiety and stress-related disorders. In addition, the data given here show that protein levels of brain-derived neurotrophic factor (BDNF) are elevated in the hippocampus of mGluR7-/- mice which will be discussed at the latter part of this thesis in the context of the stress-resistant phenotype found in those animals. It can be concluded that genetic ablation of mGluR7 in mice interferes at multiple sites in the neuronal circuitry and molecular pathways implicated in anxiety and stress-related disorders. Metabotropic glutamate receptor subtypes (mGluR1 to -8) act as pre- and postsynaptic regulators of neurotransmission in the central nervous system. Regulation of neurotransmission via metabotropic glutamate receptors has recently been implicated in the pathophysiology of anxiety and stress-related disorders including depression. Among metabotropic glutamate receptor subtypes, the group III metabotropic glutamate receptor subtype 7 (mGluR7) shows the highest evolutionary conservation (Flor et al., 1997; Makoff et al., 1996), which suggests that this receptor could play an important physiological role. Cryan et al. (2003) have demonstrated that mice with a targeted deletion of the gene for mGluR7 (mGluR7-/-) show antidepressant and anxiolytic-like effects in a variety of stress-related paradigms, including the forced swim stress and the stress-induced hyperthermia tests. Furthermore, the same group has recently developed mGluR7 knockdown using siRNA, which further supported the critical role of mGluR7 in anxiety- and stress-related behaviors (Thakker et al., 2005). Since the hypothalamic-pituitary-adrenal (HPA) axis regulates stress responses, it was investigated in this thesis whether the levels of selected mRNA transcripts and endocrine hormones were altered in mGluR7 deficient mice in the HPA axis. Over all, mGluR7-/- mice showed only moderately lower serum levels of corticosterone and adrenocorticotropic hormone (ACTH) compared to mGluR7+/+ mice. However, strong evidence has been found for up-regulation of glucocorticoid receptor (GR)-dependent feedback suppression of the HPA axis in mice with mGluR7 deficiency: (i) mRNA transcripts of GR were significantly higher in the hippocampus of mGluR7-/- animals, (ii) similar increases were seen for 5-HT1A receptor transcripts which are thought to be directly controlled by the GR transcription factor and finally (iii) mGluR7-/- 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-/- mice in animal models for anxiety and stress-related disorders. In addition, the data given here show that protein levels of brain-derived neurotrophic factor (BDNF) are elevated in the hippocampus of mGluR7-/- mice which will be discussed at the latter part of this thesis in the context of the stress-resistant phenotype found in those animals. It can be concluded that genetic ablation of mGluR7 in mice interferes at multiple sites in the neuronal circuitry and molecular pathways implicated in anxiety and stress-related disorders

Metabotropic glutamate receptor subtype 7 ablation causes dysregulation of the HPA axis and increases hippocampal BDNF protein levels: implications for stress-related psychiatric disorders.

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-/-) 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-/- 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-/- animals, (ii) similar increases were seen with 5-HT1A receptor transcripts, which are thought to be directly controlled by the transcription factor GR and finally (iii) mGluR7-/- 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-/- 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-/- 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

mGluR7 facilitates extinction of aversive memories and controls amygdala plasticity

Formation and extinction of aversive memories in the mammalian brain are insufficiently understood at the cellular and molecular levels. Using the novel metabotropic glutamate receptor 7 (mGluR7) agonist AMN082, we demonstrate that mGluR7 activation facilitates the extinction of aversive memories in two different amygdala-dependent tasks. Conversely, mGluR7 knockdown using short interfering RNA attenuated the extinction of learned aversion. mGluR7 activation also blocked the acquisition of Pavlovian fear learning and its electrophysiological correlate long-term potentiation in the amygdala. The finding that mGluR7 critically regulates extinction, in addition to acquisition of aversive memories, demonstrates that this receptor may be relevant for the manifestation and treatment of anxiety disorders