Metabotropic glutamate receptor subtype 7 controls maternal care, maternal motivation and maternal aggression in mice

The group III metabotropic glutamate receptor subtype 7 (mGlu7) is an important regulator of glutamatergic and GABAergic neurotransmission and known to mediate emotionality and male social behavior. However, a possible regulatory role in maternal behavior remains unknown to date. Adequate expression of maternal behavior is essential for successful rearing and healthy development of the young. By understanding genetic and neural mechanisms underlying this important prosocial behavior, we gain valuable insights into possible dysregulations. Using genetic ablation as well as pharmacological modulation, we studied various parameters of maternal behavior in two different mouse strains under the influence of mGlu7. We can clearly show a regulatory role of mGlu7 in maternal behavior. Naive virgin female C57BL/6 mGlu7 knockout mice showed more often nursing postures and less spontaneous maternal aggression compared to their heterozygous and wildtype littermates. In lactating C57BL/6 wildtype mice, acute central activation of mGlu7 by the selective agonist AMN082 reduced arched back nursing and accelerated pup retrieval without affecting maternal aggression. In addition, in lactating CD1 wildtype mice the selective mGlu7 antagonist XAP044 increased both pup retrieval and maternal aggression. With respect to receptor expression levels, mGlu7 mRNA expression was higher in lactating vs virgin C57BL/6 mice in the prefrontal cortex, but not hypothalamus or hippocampus. In conclusion, these findings highlight a significant role of the mGlu7 receptor subtype in mediating maternal behavior in mice. Region-dependent studies are warranted to further extend our knowledge on the specific function of the brain glutamate system in maternal behavior

Blocking Metabotropic Glutamate Receptor Subtype 7 via the Venus Flytrap Domain Promotes a Chronic Stress-Resilient Phenotype in Mice

Chronic psychosocial stress participates prominently in the etiology of various psychiatric conditions and comorbid somatic pathologies; however, suitable pharmacotherapy of these disorders is still of high medical need. During the last few decades, research on mGlu receptors advanced remarkably and much attention was given to the mGlu7 subtype. Here, genetic mGlu7 ablation, short-term pharmacological mGlu7 blockade, as well as siRNA-mediated knockdown of mGlu7 were shown to result in an acute anti-stress, antidepressant- and anxiolytic-like phenotype in mice. Moreover, we recently revealed a prominent stress-protective effect of genetic mGlu7 ablation also with respect to chronic psychosocial stress. In addition, we are able to demonstrate in the present study that the chronic pharmacological blockade of mGlu7 interferes with various chronic stress-induced alterations. For this, we used the chronic subordinate colony housing (CSC), a mouse model of chronic male subordination, in combination with chronic treatment with the mGlu7-selective orthosteric-like antagonist XAP044 (7-hydroxy-3-(4-iodophenoxy)-4H-chromen-4-one). Interestingly, XAP044 dose-dependently ameliorates hypothalamic–pituitary–adrenal axis dysfunctions, thymus atrophy, as well as the CSC-induced increase in innate anxiety. Taken together, our findings provide further evidence for the role of mGlu7 in chronic psychosocial stress-induced alterations and suggests the pharmacological blockade of mGlu7 as a promising therapeutic approach for the treatment of chronic stress-related pathologies in me

The Emerging Role of Metabotropic Glutamate Receptors in the Pathophysiology of Chronic Stress-Related Disorders

Chronic stress-related psychiatric conditions such as anxiety, depression, and alcohol abuse are an enormous public health concern. The etiology of these pathologies is complex, with psychosocial stressors being among the most frequently discussed risk factors. The brain glutamatergic neurotransmitter system has often been found involved in behaviors and pathophysiologies resulting from acute stress and fear. Despite this, relatively little is known about the role of glutamatergic system components in chronic psychosocial stress, neither in rodents nor in humans. Recently, drug discovery efforts at the metabotropic receptor subtypes of the glutamatergic system (mGlu1-8 receptors) led to the identification of pharmacological tools with emerging potential in psychiatric conditions. But again, the contribution of individual mGlu subtypes to the manifestation of physiological, molecular, and behavioral consequences of chronic psychosocial stress remains still largely unaddressed. The current review will describe animal models typically used to analyze acute and particularly chronic stress conditions, including models of psychosocial stress, and there we will discuss the emerging roles for mGlu receptor subtypes. Indeed, accumulating evidence indicates relevance and potential therapeutic usefulness of mGlu2/3 ligands and mGlu5 receptor antagonists in chronic stress-related disorders. In addition, a role for further mechanisms, e.g. mGlu7-selective compounds, is beginning to emerge. These mechanisms are important to be analyzed in chronic psychosocial stress paradigms, e.g. in the chronic subordinate colony housing (CSC) model. We summarize the early results and discuss necessary future investigations, especially for mGlu5 and mGlu7 receptor blockers, which might serve to suggest improved therapeutic strategies to treat stress-related disorders

Relief from detrimental consequences of chronic psychosocial stress in mice deficient for the metabotropic glutamate receptor subtype 7

Chronic stress-related psychiatric conditions and comorbid somatic pathologies are an enormous public health concern in modern society. The etiology of these disorders is complex, with stressors holding a chronic and psychosocial component representing the most acknowledged risk factor. During the last decades, research on the metabotropic glutamate receptor (mGlu) system advanced dramatically and much attention was given to the role of the metabotropic glutamate receptor subtype 7 (mGlu7) in acute stress related behavior and physiology. However, virtually nothing is known about the potential involvement of mGlu7 in chronic psychosocial stress-related conditions. Using the chronic subordinate colony housing (CSC, 19 days) in male mice, we addressed whether central mGlu7 is altered upon chronic psychosocial stressor exposure and whether genetic ablation of mGlu7 interferes with the multitude of chronic stress induced alterations. CSC exposure resulted in a downregulation of mGlu7 mRNA transcript levels in the prefrontal cortex, a brain region relevant for stress-related behaviors and physiology. Interestingly, mGlu7 deficiency relieved multiple chronic stress-induced alterations including the CSC-induced anxiety-prone phenotype; mGlu7 ablation also ameliorated CSC-induced physiological and immunological consequences such as hypothalamo-pituitary-adrenal (HPA) axis dysfunctions and colonic inflammation, respectively. Together, our findings provide first evidence for the involvement of mGlu7 in a wide range of behavioral and physiological alterations in response to chronic psychosocial stressor exposure. Moreover, the stress-protective phenotype of genetic mGlu7 ablation suggests mGlu7 pharmacological blockade to be a relevant option for the treatment of chronic stress-related emotional and somatic dysfunctions. This article is part of the Special Issue entitled 'Metabotropic Glutamate Receptors, 5 years on'. (C) 2016 Elsevier Ltd. All rights reserved

Adrenal gland plasticity in lactating rats and mice is sufficient to maintain basal hypersecretion of corticosterone

Increased basal glucocorticoid secretion and a reduced glucocorticoid response during acute stress, despite only minor changes in the secretion of the major secretagogue adrenocorticotropic hormone (ACTH), have been documented in the peripartum period in several species. We recently showed that the adrenal gland, the site of glucocorticoid synthesis, undergoes substantial postpartum-associated plasticity in the rat at mid-lactation. Here, we asked the question whether adrenal changes already take place around parturition in the rat and in another species, namely the mouse. After demonstrating that several components of the adrenal machinery mediating cholesterol supply for steroidogenesis, including protein levels of hormone-sensitive lipase, low-density lipoprotein receptor (LDLR) and scavenger receptor class-B type-1 (SRB1), are upregulated, while hydroxymethylglutaryl coenzyme A reductase (HMGCR) is downregulated in the lactating rat one day after delivery, as previously observed at mid-lactation, we demonstrated profound changes in the mouse. In detail, protein expression of LDLR, SRB1, HMGCR and adrenal lipid store density were increased in the mouse adrenal one day after parturition as tested via western blot analysis and oil-red lipid staining, respectively. Moreover, using in vitro culture techniques, we observed that isolated adrenal explants from lactating mice secreted higher levels of corticosterone under basal conditions, but showed impaired responsiveness to ACTH, mimicking the in vivo scenario. These results suggest that mechanisms of adaptation in the maternal adrenal after delivery, namely increased cholesterol availability and decreased ACTH sensitivity, are crucial for the basal increase in circulating glucocorticoids and maternal stress hyporesponsiveness that are typical of this period

Blocking metabotropic glutamate receptor subtype 5 relieves maladaptive chronic stress consequences

Etiology and pharmacotherapy of stress-related psychiatric conditions and somatoform disorders are areas of high unmet medical need. Stressors holding chronic plus psychosocial components thereby bear the highest health risk. Although the metabotropic glutamate receptor subtype 5 (mGlu5) is well studied in the context of acute stress-induced behaviors and physiology, virtually nothing is known about its potential involvement in chronic psychosocial stress. Using the mGlu5 negative allosteric modulator CTEP (2-chloro-4[2-[2,5-dimethy1-1-[4-(trifluoromethoxy)phenylilmidazol-4yl]ethynyl]pyridine), a close analogue of the clinically active drug basimglurant- but optimized for rodent studies, as well as mGlu5-deficient mice in combination with a mouse model of male subordination (termed CSC, chronic subordinate colony housing), we demonstrate that mGlu5 mediates multiple physiological, immunological, and behavioral consequences of chronic psychosocial stressor exposure. For instance, CTEP dose dependently relieved hypothalamo-pituitary-adrenal axis dysfunctions, colonic inflammation as well as the CSC-induced increase in innate anxiety; genetic ablation of mGlu5 in mice largely reproduced the stress-protective effects of CTEP and additionally ameliorated CSC-induced physiological anxiety. Interestingly, CSC also induced an upregulation of mGlu5 in the hippocampus, a stress-regulating brain area. Taken together, our findings provide evidence that mGlu5 is an important mediator for a wide range of chronic psychosocial stress-induced alterations and a potentially valuable drug target for the treatment of chronic stress-related pathologies in man. (C) 2016 Elsevier Inc. All rights reserved

Type-7 metabotropic glutamate receptors negatively regulate α 1 -adrenergic receptor signalling

We studied the interaction between mGlu7 and alpha(1)-adrenergic receptors in heterologous expression systems, brain slices, and living animals. L-2-Amino-4-phosphonobutanoate (L-AP4), and L-serine-O-phosphate (L-SOP), which activate group III mGlu receptors, restrained the stimulation of polyphosphoinositide (PI) hydrolysis induced by the alpha(1)-adrenergic receptor agonist, phenylephrine, in HEK 293 cells co-expressing alpha(1)-adrenergic and mGlu7 receptors. The inibitory action of L-AP4 was abrogated by (i) the mGlu7 receptor antagonist, XAP044; (ii) the C-terminal portion of type-2 G protein coupled receptor kinase; and (iii) the MAP kinase inhibitors, U0126 and PD98059. This suggests that the functional interaction between mGlu7 and alpha(1)-adrenergic receptors was mediated by the beta gamma-subunits of the G(i) protein and required the activation of the MAP kinase pathway. Remarkably, activation of neither mGlu2 nor mGlu4 receptors reduced alpha(1)-adrenergic receptor-mediated PI hydrolysis. In mouse cortical slices, both L-AP4 and L-SOP were able to attenuate norepinephrine- and phenylephrine-stimulated PI hydrolysis at concentrations consistent with the activation of mGlu7 receptors. L-AP4 failed to affect norepinephrine-stimulated PI hydrolysis in cortical slices from mGlu7(-/-) mice, but retained its inhibitory activity in slices from mGlu4(-/-) mice. At behavioural level, i.c.v. injection of phenylephrine produced antidepressant-like effects in the forced swim test. The action of phenylephrine was attenuated by L-SOP, which was inactive per se. Finally, both phenylephrine and L-SOP increased corticosterone levels in mice, but the increase was halved when the two drugs were administered in combination. Our data demonstrate that alpha(1)-adrenergic and mGlu7 receptors functionally interact and suggest that this interaction might be targeted in the treatment of stress-related disorders. (C) 2016 Elsevier Ltd. All rights reserved

Individual differences in stress vulnerability: The role of gut pathobionts in stress-induced colitis

Chronic subordinate colony housing (CSC), an established mouse model for chronic psychosocial stress, promotes a microbial signature of gut inflammation, characterized by expansion of Proteobacteria, specifically Helicobacter spp., in association with colitis development. However, whether the presence of Helicobacter spp. during CSC is critically required for colitis development is unknown. Notably, during previous CSC studies performed at Regensburg University (University 1), male specific-pathogen-free (SPF) CSC mice lived in continuous subordination to a physically present and Helicobacter spp.-positive resident. Therefore, it is likely that CSC mice were colonized, during the CSC procedure, with Helicobacter spp. originating from the dominant resident. In the present study we show that employing SPF CSC mice and Helicobacter spp.-free SPF residents at Ulm University (University 2), results in physiological responses that are typical of chronic psychosocial stress, including increased adrenal and decreased thymus weights, decreased adrenal in vitro adrenocorticotropic hormone (ACTH) responsiveness, and increased anxiety-related behavior. However, in contrast to previous studies that used Helicobacter spp.-positive resident mice, use of Helicobacter spp.-negative resident mice failed to induce spontaneous colitis in SPF CSC mice. Consistent with the hypothesis that the latter is due to a lack of Helicobacter spp. transmission from dominant residents to subordinate mice during the CSC procedure, colonization of SPF residents with Helicobacter typhlonius at University 2, prior to the start of the CSC model, rescued the colitis-inducing potential of CSC exposure. Furthermore, using SPF CSC mice and H. typhlonius-free SPF residents at University 1 prevented CSC-induced colitis. In summary, our data support the hypothesis that the presence or absence of exposure to certain pathobionts contributes to individual variability in susceptibility to stress-/trauma-associated pathologies and to reproducibility of stress-related outcomes between laboratories. Keywords: Chronic psychosocial stress; Chronic subordinate colony housing (CSC); Enterohepatic Helicobacter species (EHS); Inflammatory bowel disease (IBD); Microbiota; Colitis; Stress vulnerability; Stress resilience; Inflammation; Pathobiont

Individual differences in stress vulnerability: The role of gut pathobionts in stress-induced colitis

Chronic subordinate colony housing (CSC), an established mouse model for chronic psychosocial stress, promotes a microbial signature of gut inflammation, characterized by expansion of Proteobacteria, specifically Helicobacter spp., in association with colitis development. However, whether the presence of Helicobacter spp. during CSC is critically required for colitis development is unknown. Notably, during previous CSC studies performed at Regensburg University (University 1), male specific-pathogen-free (SPF) CSC mice lived in continuous subordination to a physically present and Helicobacter spp.-positive resident. Therefore, it is likely that CSC mice were colonized, during the CSC procedure, with Helicobacter spp. originating from the dominant resident. In the present study we show that employing SPF CSC mice and Helicobacter spp.-free SPF residents at Ulm University (University 2), results in physiological responses that are typical of chronic psychosocial stress, including increased adrenal and decreased thymus weights, decreased adrenal in vitro adrenocorticotropic hormone (ACTH) responsiveness, and increased anxiety-related behavior. However, in contrast to previous studies that used Helicobacter spp.-positive resident mice, use of Helicobacter spp.-negative resident mice failed to induce spontaneous colitis in SPF CSC mice. Consistent with the hypothesis that the latter is due to a lack of Helicobacter spp. transmission from dominant residents to subordinate mice during the CSC procedure, colonization of SPF residents with Helicobacter typhlonius at University 2, prior to the start of the CSC model, rescued the colitis-inducing potential of CSC exposure. Furthermore, using SPF CSC mice and H. typhlonius-free SPF residents at University 1 prevented CSC-induced colitis. In summary, our data support the hypothesis that the presence or absence of exposure to certain pathobionts contributes to individual variability in susceptibility to stress-/trauma-associated pathologies and to reproducibility of stress-related outcomes between laboratories. (C) 2016 Elsevier Inc. All rights reserved