Novel antidepressant targets in affective disorders

Current antidepressant treatment strategies targeting monoamine systems display clear disadvantages including insufficient efficacy, delayed onset of action and a number of side effects that limit compliance. Given the increasing significance of depression and related disorders, there is an urgent demand for novel and more effective treatments. The overall aim of this project is to identify targets beyond monoamine signaling in innovative, etiologically and clinically relevant rodent models of induced depression [magnesium (Mg) deficient mice], as well as of innate depression such as the enhanced anxiety and comorbid depression related behavior (HAB) mice and the Flinders sensitive rat line (FSL). The core to success of the proposed project is the combination of hypothesis- driven, as well as unbiased approaches using up-to date methodology including genetically modified mice, functional imaging and proteomics. As mounting evidence suggests that treatments antagonizing N-methyl-D- aspartate (NMDA) receptors may induce rapid and enduring antidepressant effects, we will first focus on this system and investigate whether it is possible to normalize enhanced depression-like behaviors and associated aberrant brain activation patterns by antagonizing normal NMDA receptor function. In addition to NMDAR antagonists such as ketamine, also effects of mild NMDAR antagonism (e.g. by Mg supplementation) alone or as augmentation of ineffective SSRI treatment in HABs, will be studied. Subsequently, using a combination of pharmacological and genetic techniques, we will determine the local contribution of individual NMDA receptor subunits (NR1, NR2A, NR2B) to the enhanced depression-related behavior in our mouse models. A parallel non- hypothesis driven approach, proteomic analysis in the identified candidate brain areas of Mg deficient mice, will reveal altered expression of proteins beyond NMDA receptor signaling. Pharmacological approaches will be used to demonstrate causality of identified affected neurobiological systems contributing to enhanced depression-like behavior. This information will be essential to establish novel drug targets for the development of antidepressants beyond the monoaminergic systems targeted up to date.

Current antidepressant treatment strategies for depression and anxiety disorders, targeting monoamine systems, have clear limitations, including insufficient efficacy, delayed onset of action and a number of side effects that limit compliance. Given the increasing significance of depression and related disorders, there is an urgent demand for novel treatment approaches. The overall aim of this project was to investigate and identify targets beyond monoamine signaling in etiologically and clinically relevant rodent models of i) dietary-induced or ii) innate anxiety and depression (HAB model). Based on the observed association of low brain magnesium (Mg) levels with treatment-resistant (i.e. not responsive to monoamine-targeted antidepressants) depression in humans, we could show that dietary magnesium restriction (MgR) leads to lower brain Mg and enhanced depression-like behavior in different mouse strains as well as in the rat suggesting experimentally-induced MgR as a robust rodent model of depression. We identified aberrant challenge-induced neuronal activation in the amygdala, a brain region involved in emotional processing, as one common neural substrate of the MgR induced-, as well as the innate pro-depressive phenotype. We found that the N-methly-D-aspartate receptor (NMDAR) signaling pathway within the amygdala was associated with the MgR-induced pro-depressive phenotype. Specifically, the NR1 subunit of the NMDAR and the downstream neuronal nitric oxide synthase/nitric oxide signaling pathway were demonstrated to be involved in MgR-induced depression-like behavior. Treatment with the NMDAR antagonist ketamine or with magnesium supplementation led to beneficial therapeutic responses in both models of depression (innate and induced), as did treatment with clinically established anxiolytics/antidepressants such as diazepam, desipramine. In addition, these treatments also normalized the aberrant changes pointing to an overactivation of the NMDAR/nitric oxide pathway in the amygdala of MgR mice. Our data provide the first evidence that MgR rodents represent a novel depression model based on chronic activation of NMDA pathways. This model should help to identify the therapeutic potential of novel antidepressant drugs interacting with targets, not primarily based on the monoamine theory of depression, and possibly helpful in treatment-resistant forms of depression.