Daniela Felice

Early-life stress induces visceral hypersensitivity in mice.

Early-life stress is a risk factor for irritable bowel syndrome (IBS), a common and debilitating functional gastrointestinal disorder that is often co-morbid with stress-related psychiatric disorders. In the rat, maternal separation (MS) stress has been shown to induce visceral hypersensitivity in adulthood and thus has become a useful model of IBS. However, development of mouse models of maternal separation has been difficult. Given the advent of transgenic mouse technology, such models would be useful to further our understanding of the pathophysiology of IBS and to develop new pharmacological treatments. Thus, the present study aimed to develop a mouse model of MS stress-induced visceral hyperalgesia as measured using manometric recordings of colorectal distension (CRD). Moreover, since the GABA(B) receptor has been reported to play a role in pain processes, we also assessed its role in visceral nociception using novel GABA(B(1b)) receptor subunit knockout mice. CRD was performed in adult male wildtype and GABA(B(1b)) receptor knockout mice that had undergone unpredictable MS combined with unpredictable maternal stress (MSUS) from postnatal day 1 through 14 (PND 1-14). MSUS induced visceral hypersensitivity in both wildtype and GABA(B(1b)) receptor knockout mice when compared with non-stressed mice. Wildtype and GABA(B(1b)) receptor knockout mice did not differ in baseline or stress-induced visceral sensitivity. To the best of our knowledge, this is the first study to show that early-life stress induces visceral hypersensitivity in a mouse model. These findings may provide a novel mouse model of visceral hypersensitivity which may aid our understanding of its underlying mechanisms in future studies.

GABAB(1) receptor subunit isoforms differentially regulate stress resilience.

Significance Stress can increase susceptibility to developing psychiatric disorders, including depression. Understanding the neurobiological mechanisms underlying stress resilience and susceptibility is key to identifying novel targets for the development of more effective treatments for stress-related psychiatric disorders. Here we show that specific isoforms of GABAB receptor subunits differentially regulate stress resilience. Specifically, GABAB(1a)−/− mice are more susceptible whereas GABAB(1b)−/− mice are more resilient to stress-induced anhedonia and psychosocial stress-induced social withdrawal, two features of depression. Furthermore, GABAB(1b)−/− mice were resilient to stress-induced decreases in the survival of newly born cells in the adult hippocampus, and hippocampal GABAB(1b) expression was increased in a genetic mouse model of depression. Taken together, GABAB receptor subunit isoforms may represent novel therapeutic targets for stress-related disorders. Stressful life events increase the susceptibility to developing psychiatric disorders such as depression; however, many individuals are resilient to such negative effects of stress. Determining the neurobiology underlying this resilience is instrumental to the development of novel and more effective treatments for stress-related psychiatric disorders. GABAB receptors are emerging therapeutic targets for the treatment of stress-related disorders such as depression. These receptors are predominantly expressed as heterodimers of a GABAB(2) subunit with either a GABAB(1a) or a GABAB(1b) subunit. Here we show that mice lacking the GABAB(1b) receptor isoform are more resilient to both early-life stress and chronic psychosocial stress in adulthood, whereas mice lacking GABAB(1a) receptors are more susceptible to stress-induced anhedonia and social avoidance compared with wild-type mice. In addition, increased hippocampal expression of the GABAB(1b) receptor subunit is associated with a depression-like phenotype in the helpless H/Rouen genetic mouse model of depression. Stress resilience in GABAB(1b)−/− mice is coupled with increased proliferation and survival of newly born cells in the adult ventral hippocampus and increased stress-induced c-Fos activation in the hippocampus following early-life stress. Taken together, the data suggest that GABAB(1) receptor subunit isoforms differentially regulate the deleterious effects of stress and, thus, may be important therapeutic targets for the treatment of depression.

Vortioxetine for the treatment of major depressive disorder

Vortioxetine (Brintellix®, 1-[2-(2,4-dimethylphenyl-sulfanyl)-phenyl]-piperazine) is a multimodal antidepressant targeting the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT3, 5-HT7 receptors and the serotonin (5-HT) transporter (5-HTT). Vortioxetine administration induces antidepressant- and anxiolytic-like effects, and can enhance cognitive performance in rodents. Several clinical trials have reported the efficiency and a satisfactory tolerability of vortioxetine treatment in depressed patients. Remarkably, vortioxetine has a specific positive impact on cognitive symptoms in depressed patients. Overall, vortioxetine is an efficacious antidepressant drug for the treatment of patients with a major depressive episode and has a unique mechanism of action offering a new therapeutic option.

The vagus nerve modulates BDNF expression and neurogenesis in the hippocampus

Accumulating evidence suggests that certain gut microbiota have antidepressant-like behavioural effects and that the microbiota can regulate neurogenesis and the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. The precise mechanisms underlying these effects are not yet clear. However, the vagus nerve is one of the primary bidirectional routes of communication between the gut and the brain and thus may represent a candidate mechanism. Yet, relatively little is known about the direct influence of vagus nerve activity on hippocampal function and plasticity. Thus, the aim of the present study was to determine whether constitutive vagus nerve activity contributes to the regulation of neurogenesis and BDNF mRNA expression in the hippocampus. To this end, we examined the impact of subdiaphragmatic vagotomy in adult mice on these parameters. We found that vagotomy decreased BDNF mRNA in all areas of the hippocampus. Vagotomy also reduced the proliferation and survival of newly born cells and decreased the number of immature neurons, particularly those with a more complex dendritic morphology. Taken together, these findings suggest that vagal nerve activity influences neurogenesis and BDNF mRNA expression in the adult hippocampus.

Targeting the GABA B Receptor for the Treatment of Depression and Anxiety Disorders

The GABAB receptor is a functional heterodimer comprising the GABAB1 and GABAB2 subunits, with the GABAB1 subunit displaying two major isoforms, GABAB(1a) and GABAB(1b). Since the discovery of the GABAB receptor by Bowery in 1980, preclinical and clinical findings have strongly implicated the GABAB receptor in depression and anxiety disorders. Indeed, postmortem and clinical studies have highlighted a key role for the GABAB receptor in mood disorders. In parallel, pharmacological and genetic preclinical studies have confirmed that the GABAB receptor can modulate anxiety and depression-related behaviours. Despite the literature clearly linking GABAB receptor dysfunction with depression and anxiety disorders, GABAB receptor-based drugs have not yet been approved for their treatment. One of the main reasons for this is that drugs targeting the whole GABAB receptor may induce several major side effects. However, positive allosteric modulators and more recently, negative allosteric modulators of the GABAB receptor have been developed, and these could represent future therapeutic approaches for depression and anxiety disorders. Moreover, recent studies suggest that proteins interacting with the GABAB receptor could also be valid targets for the development of GABAB receptor-based drugs. This chapter will review the preclinical and clinical evidence for the GABAB receptor as a therapeutic target in the treatment of depression and anxiety disorders, and will outline some of the challenges that need to be overcome before GABAB receptor-based drugs can be used for this purpose in the clinic.

Vortioxetine Improves Context Discrimination in Mice Through a Neurogenesis Independent Mechanism

Major Depressive Disorders (MDD) patients may exhibit cognitive deficits and it is currently unclear to which degree treatment with antidepressants may affect cognitive function. Preclinical and clinical observations showed that vortioxetine (VORT, an antidepressant with multimodal activity), presents beneficial effects on aspects of cognitive function. In addition, VORT treatment increases adult hippocampal neurogenesis (AHN) in rodents, a candidate mechanism for antidepressant activity. Pattern separation (PS) is the ability to discriminate between two similar contexts/events generating two distinct and non-overlapping representations. Impaired PS may lead to overgeneralization and anxiety disorders. If PS impairments were described in depressed patients, the consequences of antidepressant treatment on context discrimination (CD) are still in its infancy. We hypothesized that VORT-increased AHN may improve CD. Thus, in an attempt to elucidate the molecular mechanism underpinning VORT treatment effects on CD, a rodent model of PS, the role of AHN and stress-induced c-Fos activation was evaluated in the adult mouse hippocampus. Chronic treatment with VORT (1.8 g/kg of food weight; corresponding to a daily dose of 10 mg/kg, 3 weeks) improved CD in mice. Interestingly, chronic treatment with VORT reversed ablation of AHN-induced delay in CD and freezing behavior. VORT treatment decreased stress-induced c-Fos activation in the dorsal but not ventral dentate gyrus. VORT treatment did not affect c-Fos activity in the hippocampus of mice with ablated neurogenesis. This study highlights a role of VORT in CD, which may be independent from AHN and hippocampal c-Fos activation. Further studies elucidating the mechanisms underlying VORT’s effects in CD could contribute to future strategies for alleviating the disease burden for individuals suffering from depression and/or anxiety disorders.

P.2.b.016 GABAB receptor subunit isoforms differentially mediate susceptibility to early-life stress-induced depression-related behaviour

References: 1. Caspi A. et al., Science, 2003. 301(5631): p. 386-9; 2. Cryan, J.F. and K. Kaupmann, Trends Pharmacol Sci, 2005. 26(1): p. 36-43. 3. Jacobson, L.H., et al., J Neurosci, 2006. 26(34): p. 8800-3; 4. Franklin T.B. , et al., Biol Psychiatry. 2010 Sep 1;68(5):408-15. 5. Bannerman D.M. et al., Neurosci Biobehav Rev. 2004;28(3):273-83 Acknowledgements: Supported by FP7 DEVANX – HEALTH-F2-2007-201714 (J.F.C.), Health Research Board Ireland (PD/2008/26;O.F.O) • Recent evidence suggests that interactions between genetic risk factors and adverse environmental conditions, particularly during early-life, are important risk factors for the development of depression and anxiety disorders1.