Pulmonary maternal immune activation does not cross the placenta but leads to fetal metabolic adaptation.

The fetal development of organs and functions is vulnerable to perturbation by maternal inflammation which may increase susceptibility to disorders after birth. Because it is not well understood how the placenta and fetus respond to acute lung- inflammation, we characterize the response to maternal pulmonary lipopolysaccharide exposure across 24 h in maternal and fetal organs using multi-omics, imaging and integrative analyses. Unlike maternal organs, which mount strong inflammatory immune responses, the placenta upregulates immuno-modulatory genes, in particular the IL-6 signaling suppressor Socs3. Similarly, we observe no immune response in the fetal liver, which instead displays metabolic changes, including increases in lipids containing docosahexaenoic acid, crucial for fetal brain development. The maternal liver and plasma display similar metabolic alterations, potentially increasing bioavailability of docosahexaenoic acid for the mother and fetus. Thus, our integrated temporal analysis shows that systemic inflammation in the mother leads to a metabolic perturbation in the fetus.

Subacute effects of a single dose of psilocybin on biomarkers of inflammation in healthy humans: An open-label preliminary investigation.

Rationale: Psilocybin is a serotonergic psychedelic that has gained prominent attention recently as a potential therapeutic for neuropsychiatric disorders including Major Depressive Disorder. Pre-clinical and initial studies in humans suggest that serotonin 2A receptor agonists, including serotonergic psychedelics, have anti-inflammatory effects. This may contribute to its therapeutic effects as previous studies indicate a link between neuropsychiatric disorders and inflammatory processes. However, the effect of psilocybin on biomarkers of inflammation has not been evaluated in humans. Objectives: Investigate the effect of a single dose of psilocybin on peripheral biomarkers of inflammation in healthy humans. Methods: Blood samples were collected from 16 healthy participants before and one day after the administration of a single oral dose of psilocybin (mean dose: 0.22 mg/kg) and subsequently analyzed for concentrations of high-sensitivity C-reactive protein (hsCRP), tumor-necrosis-factor (TNF) and soluble urokinase plasminogen activator receptor (suPAR). Change in inflammatory markers was evaluated using a paired t-test where p < 0.05 was considered statistically significant. Results: We did not observe statistically significant changes in any of the above biomarkers of inflammation (all Cohen's d ≤ 0.31; all p ≥ 0.23). Conclusions: Our data do not support that a single dose of psilocybin reduces biomarkers of inflammation in healthy individuals one day after administration. Nevertheless, we suggest that future studies consider additional markers of inflammation, including markers of neuroinflammation, and evaluate potential anti-inflammatory effects of psilocybin therapy in clinical cohorts where more prominent effects may be observable.

Single dose S-ketamine rescues transcriptional dysregulation of Mtor and Nrp2 in the prefrontal cortex of FSL rats 1 hour but not 14 days post dosing.

There is a pressing need to identify biological indicators of major depression to help guide proper diagnosis and optimize treatment. Animal models mimicking aspects of depression constitute essential tools for early-stage exploration of relevant pathways. In this study, we used the Flinders Sensitive and Resistant Line (FSL/FRL) to explore central and peripheral transcriptional changes in vascular endothelial growth factor (VEGF) pathway genes and their temporal regulation after a single dose of S-ketamine (15 mg/kg). We found that S-ketamine induced both rapid (1 hour) and sustained (2 and 14 days) antidepressant-like effects in the FSL rats. Analysis of mRNA expression revealed significant strain effects of Vegf, Vegf164, Vegfr-1, Nrp1, Nrp2, Rictor, and Raptor in the prefrontal cortex (PFC) and of Vegf164, GbetaL, and Tsc1 in the hippocampus (HIP), which indicates suppression of VEGF signaling in the FSL rats compared to FRL rats. This notion was further substantiated by reduced expression of Vegf and Mtor in plasma from FSL rats. In the brain, S-ketamine induced transcriptional changes in the acute phase, not the sustained phase. There were significant treatment effects of S-ketamine on Vegfr-2 in both PFC and HIP and on Vegf and Vegfr-1 in HIP. Moreover, we found that S-ketamine specifically restored reduced levels of Nrp2 and Mtor in the PFC of the FSL rats. In conclusion, this study substantiates the use of the FRL/FSL rats to explore the depressive-like behavior at the transcriptional level of the VEGF pathway genes and study their regulation in response to various treatment paradigms.

Depression and inflammation: Correlation between changes in inflammatory markers with antidepressant response and long-term prognosis.

Inflammation may correlate with a specific subgroup of depression and differential antidepressant response, but no trial has studied changes of many inflammatory markers over several time points and evaluated symptom-specific antidepressant response and long-term prognosis. We performed secondary analyses among 90 outpatients with moderate-severe depression (71% female, mean age 38 years) treated for 26 weeks with escitalopram or nortriptyline. We measured 27 pro- and anti-inflammatory markers at week 0, 8, 12, and 26 and calculated composite inflammation scores. Three depression rating scales were applied and symptom dimensions of depression calculated. Via Danish nationwide registers, 10 years follow-up were included on psychiatric hospital contacts, indicating relapse. Pearson correlation analyses were performed between baseline inflammatory markers and depressive symptom severity, mixed effects models during the 26-week trial, and Cox regression analyses for the register-based outcomes, adjusted for age, sex, BMI, and smoking. Baseline inflammatory markers correlated with differential severity on specific symptom dimensions but not with overall depression severity. A total of 17 of 27 inflammatory markers decreased significantly during treatment. We found no correlation between baseline nor change in inflammatory markers nor composite inflammation scores with differential treatment response on the MADRS, but small correlations between changes in inflammatory markers and differential response on neurovegetative symptoms. Findings were similar among 59 treatment-naïve patients. Inflammatory markers were not associated with differential risks for 10-year relapse. These findings support the importance of studying specific depressive symptoms to further explore the correlation between inflammation with differential antidepressant response in a subgroup of depression. Clinical Trial Registration number: GENDEP is registered at EudraCT2004-001723-38 (http://eudract.emea.europa.eu) and ISRCTN03693000 (www.controlled-trials.com).

Transcriptional regulation in the rat prefrontal cortex and hippocampus after a single administration of psilocybin.

BACKGROUND: Psilocybin is a serotonergic psychedelic found in "magic mushrooms" with a putative therapeutic potential for treatment-resistant depression, anxiety, obsessive-compulsive disorder, and addiction. In rodents, psilocybin acutely induces plasticity-related immediate early genes in cortical tissue; however, studies into the effects on subcortical regions, of different doses, and the subsequent translation of corresponding proteins are lacking. METHODS: We examined the acute effects of a single administration of psilocybin (0.5-20 mg/kg) on the expression of selected genes in the prefrontal cortex and hippocampus. In total, 46 target genes and eight reference genes were assessed using real-time quantitative polymerase chain reaction. Corresponding protein levels of the three most commonly regulated genes were assessed using Western blotting. RESULTS: In the prefrontal cortex, psilocybin increased the expression of Cebpb, c-Fos, Dups1, Fosb, Junb, Iκß-α, Nr4a1, P11, Psd95, and Sgk1, and decreased the expression of Clk1. In the hippocampus, psilocybin strongly increased the expression of Arrdc2, Dusp1, Iκß-α, and Sgk1 in a dose-dependent manner, and decreased the expression of Arc, Clk1, Egr2, and Ptgs2. Protein levels of Sgk1, Dusp1, and Iκß-α showed only partial agreement with transcriptional patterns, stressing the importance of assessing downstream translation when investigating rapid gene responses. CONCLUSION: The present study demonstrates that psilocybin rapidly induces gene expression related to neuroplasticity, biased towards the prefrontal cortex, compared to the hippocampus. Our findings provide further evidence for the rapid plasticity-promoting effects of psilocybin.

Antidepressant-like effect induced by P2X7 receptor blockade in FSL rats is associated with BDNF signalling activation.

BACKGROUND: P2X7 receptors (P2X7R) are ligand-gated ion channels activated by adenosine 5'-triphosphate (ATP), which are involved in processes that are dysfunctional in stress response and depression, such as neurotransmitter release, and neuroimmune response. Genetic and pharmacological inhibition of the P2X7R induce antidepressant-like effects in animals exposed to stress. However, the effect of P2X7R antagonism in an animal model of depression based on selective breeding has not previously been studied, and the mechanism underling the antidepressant-like effect induced by the P2X7R blockade remains unknown. AIMS: The present study aimed to: (1) determine whether P2X7R blockade induces antidepressant-like effects in the Flinders Sensitive Line (FSL) rats and, (2) investigate whether brain-derived neurotrophic factor (BDNF) signalling in the frontal cortex and hippocampus is involved in this effect. METHODS: FSL and the control Flinders Resistant Line (FRL) rats were treated with vehicle or the P2X7R antagonist A-804598 (3, 10 or 30 mg/Kg/day) for 1 or 7 days before being exposed to the forced swim test (FST). After the behavioural test, animals were decapitated, their brains were removed and the frontal cortex, ventral and dorsal hippocampus were dissected for BDNF signalling analysis. RESULTS: We found that repeated treatment with A-804598 (30 mg/Kg) reduced the immobility time in the FST and activated the BDNF signalling in the ventral hippocampus of FSL rats. CONCLUSIONS: P2X7R blockade induces an antidepressant-like effect associated with increased levels of BDNF-AKT-p70 S6 kinase in the ventral hippocampus, which may be mediated by tropomyosin-related kinase B (TRKB) receptor activation supporting the notion of P2X7R antagonism as a potential new antidepressant strategy.

Maternal High-fat Diet Programs Offspring Emotional Behavior in Adulthood.

Prenatal exposure to high-fat diet (HFD) might predispose offspring to develop metabolic and mental disorders later in life. Insight into the molecular and behavioral consequences of maternal HFD on offspring is sparse but may involve both neuroinflammation and a dysregulated neuroendocrine stress axis. Thus, the aim of this work was to: (i) investigate the influence of maternal HFD on memory, anxiety and depression-like behavior in adult offspring and (ii) identify possible biological biomarkers related to neuroinflammation and stress responses. Seven-week-old, female Sprague-Dawley rats received a control diet or a HFD eight weeks prior to conception and during gestation and lactation. We investigated the phenotype of the offspring in the in elevated plus maze, forced swim test, novel object recognition and open field test. Furthermore, hippocampal gene expression related to neuroinflammation and the stress axis was quantitated by real-time qPCR. We found that maternal HFD led to an anxiogenic offspring phenotype in the elevated plus maze, independent of sex. This behavioral alteration was accompanied by significantly higher mRNA levels of the hippocampal pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) mRNA and monocyte-chemoattractant protein-1 (MCP-1), both of which correlated with degree of behavioral change. Maternal exposure to HFD increased the offspring's levels of hippocampal, corticosteroid releasing hormone receptor 2 (CRHR2) and kynurenine mono oxygenase (KMO) mRNA, whereas kynurenine aminotransferase I (KAT1) mRNA levels were decreased. The present results suggest that neuroinflammatory and stress axis pathways in the hippocampus may contribute to anxiogenic effects of maternal HFD in offspring.

TNFα-dependent anhedonia and upregulation of hippocampal serotonin transporter activity in a mouse model of collagen-induced arthritis.

The serotonin transporter (SERT) facilitates high affinity reuptake of 5-HT from the extracellular fluid and dysregulation of transporter function has been implicated in a range of mood disorders including depression. Recent studies have linked immune system activation to depression as well as to altered serotonin transporter activity. Advancing previous studies, which have mainly focussed on acute effects of immune system activation, in this study we used collagen-induced arthritis (CIA) in mice as a model of chronic inflammatory disease, to investigate the effect of prolonged inflammation on brain SERT function and behaviour. We found that 5-6 weeks after immunisation, CIA mice display anhedonia, a core depression-like behaviour. Behavioural symptoms are temporally correlated with a region-specific upregulation of SERT activity in the hippocampus, which occurs at a post-translational level and is independent of SERT trafficking. Kinetic analysis of 5-HT uptake revealed that the elevation of transporter activity is due to an increase in 5-HT transport capacity (Vmax) with no change in apparent Km values, suggesting that different regulatory mechanisms govern SERT modulation under chronic versus acute inflammatory conditions. Protein expression of tumour necrosis factor receptor 1 (TNFR1) was specifically upregulated in the hippocampus of CIA mice, indicating altered TNFα signalling. Anti-TNFα treatment using etanercept not only diminished joint inflammation, but also prevented the development of anhedonia and the upregulation of SERT activity in the hippocampus, suggesting a key role for TNFα signalling in brain function regulation in this disease model. Our study provides novel insight into molecular mechanisms underlying mood symptoms in chronic inflammatory diseases, with particular relevance to rheumatoid arthritis.

A Critical Role of Mitochondria in BDNF-Associated Synaptic Plasticity After One-Week Vortioxetine Treatment.

Background: Preclinical studies have indicated that antidepressant effect of vortioxetine involves increased synaptic plasticity and promotion of spine maturation. Mitochondria dysfunction may contribute to the pathophysiological basis of major depressive disorder. Taking into consideration that vortioxetine increases spine number and dendritic branching in hippocampus CA1 faster than fluoxetine, we hypothesize that new spines induced by vortioxetine can rapidly form functional synapses by mitochondrial support, accompanied by increased brain-derived neurotrophic factor signaling. Methods: Rats were treated for 1 week with vortioxetine or fluoxetine at pharmacologically relevant doses. Number of synapses and mitochondria in hippocampus CA1 were quantified by electron microscopy. Brain-derived neurotrophic factor protein levels were visualized with immunohistochemistry. Gene and protein expression of synapse and mitochondria-related markers were investigated with real-time quantitative polymerase chain reaction and immunoblotting. Results: Vortioxetine increased number of synapses and mitochondria significantly, whereas fluoxetine had no effect after 1-week dosing. BDNF levels in hippocampus DG and CA1 were significantly higher after vortioxetine treatment. Gene expression levels of Rac1 after vortioxetine treatment were significantly increased. There was a tendency towards increased gene expression levels of Drp1 and protein levels of Rac1. However, both gene and protein levels of c-Fos were significantly decreased. Furthermore, there was a significant positive correlation between BDNF levels and mitochondria and synapse numbers. Conclusion: Our results imply that mitochondria play a critical role in synaptic plasticity accompanied by increased BDNF levels. Rapid changes in BDNF levels and synaptic/mitochondria plasticity of hippocampus following vortioxetine compared with fluoxetine may be ascribed to vortioxetine's modulation of serotonin receptors.

Neurotrophic factors in depression in response to treatment.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor A (VEGF) have been suggested to play a role in the pathophysiology of depression. The neurotrophic model of depression hypothesises that the serum level of e.g. BDNF is decreased during depression and increased in response to treatment. The aim of the present study was to investigate BDNF and VEGF as potential predictors of response to antidepressant treatment. METHODS: We investigated the longitudinal associations between depression scores and serum levels of these neurotrophic factors during antidepressant treatment in 90 individuals with depression of at least moderate severity. Serum levels were measured at baseline and after 8 and 12 weeks of treatment with nortriptyline or escitalopram. RESULTS: No baseline or longitudinal correlations between depression scores and serum levels of BDNF and VEGF were found, and the baseline serum levels did not predict the MADRS depression score after 12 weeks of treatment or the improvement in depression scores. Interestingly, we observed a significant baseline and longitudinal correlation between serum levels of BDNF and VEGF. The two classes of antidepressant treatment did not affect the results differently. LIMITATIONS: Information on potential factors influencing the serum levels is missing. CONCLUSION: Our results do not support the neurotrophic model of depression, since a significant decrease in serum BDNF and VEGF levels after 12 weeks of antidepressant treatment was observed. Our study encourages future studies with large sample sizes, more observations and a longer follow-up period.

Chronic restraint stress increases the protein expression of VEGF and its receptor VEGFR-2 in the prefrontal cortex.

In the present study the central and peripheral regulation of VEGF, its cognate receptors, and regulators were examined after acute and chronic restraint stress in rats. After chronic restraint stress (6 h per day for 21 days) the protein levels of VEGF (175 ± 24%) and its receptor VEGFR-2 (169 ± 17%) increased significantly in the prefrontal cortex (A and B). mRNA levels of VEGFR-2 (132 ± 11%) were also significantly increased (D). In the hippocampus no significant changes were observed at the mRNA or protein levels. In serum there was a tendency towards increased VEGF protein expression after both acute and chronic restraint stress (C).

Dietary magnesium deficiency alters gut microbiota and leads to depressive-like behaviour.

OBJECTIVE: Gut microbiota (GM) has previously been associated with alterations in rodent behaviour, and since the GM is affected by the diet, the composition of the diet may be an important factor contributing to behavioural changes. Interestingly, a magnesium restricted diet has been shown to induce anxiety and depressive-like behaviour in humans and rodents, and it could be suggested that magnesium deficiency may mediate the effects through an altered GM. METHODS: The present study therefore fed C57BL/6 mice with a standard diet or a magnesium deficient diet (MgD) for 6 weeks, followed by behavioural testing in the forced swim test (FST) to evaluate depressive-like behaviour. An intraperitoneal glucose tolerance test (GTT) was performed 2 day after the FST to assess metabolic alterations. Neuroinflammatory markers were analysed from hippocampus. GM composition was analysed and correlated to the behaviour and hippocampal markers. RESULTS: It was found that mice exposed to MgD for 6 weeks were more immobile than control mice in the FST, suggesting an increased depressive-like behaviour. No significant difference was detected in the GTT. GM composition correlated positively with the behaviour of undisturbed C57BL/6 mice, feeding MgD diet altered the microbial composition. The altered GM correlated positively to the hippocampal interleukin-6. CONCLUSION: In conclusion, we hypothesise that imbalances of the microbiota-gut-brain axis induced by consuming a MgD diet, contributes to the development of depressive-like behaviour.

The effect of exercise on hippocampal volume and neurotrophines in patients with major depression--a randomized clinical trial.

BACKGROUND: The hippocampal volume is reduced in patients with major depression. Exercise leads to an increased hippocampal volume in schizophrenia and in healthy old adults. The effect of exercise on hippocampal volume is potentially mediated by brain derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and insulin like growth factor 1 (IGF-1). The aim of this trial was to assess the effect of an aerobic exercise intervention on hippocampal volume and serum BDNF, VEGF, and IGF-1 in patients with major depression. METHODS: Patients were randomized to an aerobic exercise intervention (n=41) or a control condition (n=38). Both interventions consisted of three supervised sessions per week during a three months period. RESULTS: Post-intervention the increase in maximal oxygen uptake was 3.90 ml/kg/min (SD 5.1) in the aerobic exercise group and 0.95 ml/kg/min (SD 6.2) in the control group (p=0.03). The hippocampal volume, BDNF, VEGF, or IGF-1 did not differ between the two groups. Post-hoc we found a positive association between change in hippocampal volume and verbal memory (Rho=0.27; p=0.05) and change in hippocampal volume and depressive symptoms (Rho=0.30; p=0.03). LIMITATIONS: Participation was low in both groups corresponding to an average participation of one session per week. CONCLUSION: Despite a significant increase in maximal oxygen uptake, a pragmatic exercise intervention did not increase hippocampal volume or resting levels of neurotrophines in out-patients with mild to moderate major depression. Trial identifier: ClinicalTrials.gov (NCT00695552).

Depression and BMI influences the serum vascular endothelial growth factor level.

Recent studies suggest that the angiogenic cytokine vascular endothelial growth factor (VEGF) is involved in the pathogenesis of depression. However, only a few studies have investigated serum VEGF levels in individuals with depression, or the possible association between genetic variants within the VEGF gene and depression. The purpose of the present study was to investigate differences between serum VEGF levels in individuals with depression vs. control individuals, and associations between genetic markers located within VEGF and depression. In addition, determinants of the serum VEGF levels were identified. One-hundred and fifty-five depressed subjects and 280 controls were included in the study. All individuals returned a questionnaire and participated in a semi-structured diagnostic interview. Eleven single nucleotide polymorphisms were successfully analysed. VEGF levels were measured in serum by immunoassay and independent determinants of the serum VEGF level were assessed by generalized linear models.The main findings were that depression, severity of depression, previous depressive episodes, age and body mass index (BMI) were associated with higher serum VEGF levels. The genetic marker rs10434 was significantly associated with depression after correction for multiple testing, but not with the serum VEGF level. Our final model included depression and BMI as predictors of serum VEGF levels. Our study suggests a role for circulating serum VEGF in depression. Furthermore, our data also demonstrate that other factors than a diagnosis of depression influence the serum VEGF level. The importance of these factors should be emphasized when studies are compared.

The association between depressive symptoms, cognitive function, and inflammation in major depression.

The purpose of this study was to assess the association between IL-6 and CRP with depressive items and cognitive function. We included 112 outpatients with major depression from an exercise trial and 57 healthy controls. IL-6, high sensitive CRP (hsCRP), and cognitive function were assessed in all subjects. After baseline assessment, patients were randomised to either a 3months exercise intervention or an exercise control group. Post-intervention IL-6, hsCRP, depressive symptoms, and cognitive function were reassessed in the patient group. IL-6 and hsCRP were significantly increased in depressed patients compared to healthy controls (p=0.02 and 0.04). These differences were no longer significant after adjustment for lifestyle associated variables. We found no association between immune markers and specific depressive symptoms at baseline or as change over time. Regarding the cognitive tests, IL-6 was positively associated with Serial sevens (p=0.008) and hsCRP was inversely associated with Trail making A (p=0.02) and design fluency (p=0.001) at baseline. At 3months follow-up IL-6 and hsCRP levels did not significantly change from baseline and did not differ between the two patient groups. Depression scores was lower compared to baseline but did not differ between groups. Combining the two groups, a decrease in IL-6 was associated to decreased verbal fluency (p=0.02), and a decrease in hsCRP was associated with improvement in Trail making A (p=0.005). In conclusion, the level of IL-6 and hsCRP was increased in depressed outpatients but was not associated to specific depressive symptoms. In terms of cognitive function, we found that higher hsCRP levels were associated to lower psychomotor speed both at baseline and at follow-up.

Transient activation of mTOR following forced treadmill exercise in rats.

The beneficial effect of exercise on hippocampal plasticity is possibly mediated by increased angiogenesis and neurogenesis. In angiogenesis, insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), and hypoxia-inducible factor 1, alpha subunit (HIF1α) are important factors, while the induction of neurogenesis requires signaling through the VEGF receptor, Flk-1 (VEGFR-2). VEGF expression is believed to be regulated by two distinct mTOR (mammalian target of Rapamycin)-containing multiprotein complexes mTORC1 and mTORC2, respectively. This study was initiated to investigate the effect of exercise on the expression of VEGF, cognate receptors, HIF1α, mTORC1, and mTORC2 in hippocampus and frontal cortex. To this end, we measured messenger RNA (mRNA) levels in rat brain using quantitative real-time polymerase chain reaction (real-time qPCR) after forced treadmill exercise for 1 day, 2 weeks, and 8 weeks. Rats were euthanized either immediately (0 h) or 24 h after last exercise session. Here, we show that exercise affected mRNA levels of VEGF, VEGFR2, and the coreceptor neuropilin 2 (NRP2) when the rats were euthanized immediately, whereas at 24 h only the expression of mTOR was regulated after a single bout of exercise. In conclusion, the effect of treadmill exercise on the VEGF system is acute rather than chronic and there is a transient activation of mTOR. More studies are needed to understand whether this could be beneficial in the treatment of neuropsychiatric disorders.

Isolation-induced behavioural changes in a genetic animal model of depression.

Depression is a heterogeneous disorder displaying a range of symptoms including feelings of despair and social withdrawal. Social isolation may complicate the progression of depression and have effects on both behaviour and physiology. The aim of this study was to investigate the effects of social isolation on behavioural and metabolic parameters in a genetic rat model of depression, the Flinders Sensitive and Resistant Line (FSL/FRL) rats. Rats were housed either individually (social isolation) or pair-housed for 5weeks, and subjected to behavioural testing and metabolic evaluation. We found that social isolation erased the characteristic difference in depressive-like behaviour, measured as immobility in the forced swim test, between the FSL and FRL rats. Social isolation affected both strains equally in impairing object recognition memory, while leading to an increased explorative behaviour in the elevated plus maze test. Surprisingly, single-housed FRL rats showed an increased food intake compared to pair-housed FRL rats, whereas no difference in food intake or body weight was evident in FSL rats. Our results indicate that social isolation for 5weeks causes behavioural alterations, independent of strain. As the changes in appetite were only observed in the FRL rats, this may suggest that this strain responds to the stress of isolation by a change in feeding behaviour.

Electroconvulsive seizures stimulate the vegf pathway via mTORC1.

Electroconvulsive treatment (ECT) is considered the most effective treatment of depression. Recent studies demonstrate that electroconvulsive seizures (ECS), the animal variant of ECT, robustly stimulate hippocampal cell proliferation. However, the mechanisms underlying the cellular and molecular responses to ECS are not yet fully understood. A leading hypothesis of depression suggests that neurotrophic factors/growth factors play a critical role. Particularly the vascular endothelial growth factor (VEGF) is considered important, as it has been demonstrated that hippocampal VEGF expression is induced by ECS and that signaling through the VEGF receptor, Flk-1 (VEGFR2), is required for cell proliferation. VEGF expression is believed to be regulated by two distinct mTOR (mammalian Target of Rapamycin)-containing multiprotein complexes, mTORC1 and mTORC2, respectively. This study was undertaken to investigate the effect of ECS on the expression of VEGF, cognate receptors, mTORC1, and mTORC2 in the frontal cortex and the hippocampus. Using male Sprague-Dawley rats, the messenger RNA (mRNA) levels were measured by quantitative real time polymerase chain reaction (real-time qPCR) in three groups: Sham, acute (after one ECS), and repeated (ECS every day for 10 days). VEGF, VEGFR2, and components from mTORC1 were affected by repeated ECS, indicating that mediation of VEGF via mTORC1 is important for the effect of ECS.

An inhibitor of cAMP-dependent protein kinase induces behavioural and neurological antidepressant-like effects in rats.

Although it is well established that cyclic adenosine monophosphate (cAMP) signalling via cAMP-dependent protein kinase (PKA)within neurons plays an important role in depression and antidepressant treatment, the importance of several newly discovered targets that function independently from PKA, such as exchange protein activated by cAMP (Epac), remains unexplored in this regard. In this study we used a cAMP analogue that inhibits PKA but not Epac (Rp-8-Br-cAMP), to explore the modifying actions of these two targets on immobility in the forced swim test (FST) and cerebellar cAMP response element binding protein (CREB) phosphorylation in rats. In addition, we assessed central cAMP and cGMP levels and investigated the involvement of cGMP-dependent protein kinase (PKG) on any observed effects by using a selective PKG inhibitor (Rp-8-Br-PET-cGMPS).Interestingly, Rp-8-Br-cAMPS strongly reduced immobility in the FST and induced an increase in the phosphorylation of CREB in the cerebellum, effects that were unaltered by the co-administration of Rp-8-Br-PET-cGMPS. Furthermore, Rp-8-Br-cAMPS increased the accumulation of cAMP and cGMP in the hippocampus, frontal cortex and cerebellum of these rats. Together, these results suggest that in addition to activating PKA, elevated cAMP may also stimulate other targets that mediate antidepressant activity. According to the pharmacodynamic profile of Rp-8-Br-cAMPS and taking into consideration what has recently been discovered regarding the cAMP signalling system, a likely candidate is the guanine nucleotide exchange factor, Epac.