Antidepressant actions of ketamine engage cell-specific translation via eIF4E.

Effective pharmacotherapy for major depressive disorder remains a major challenge, as more than 30% of patients are resistant to the first line of treatment (selective serotonin reuptake inhibitors)1. Sub-anaesthetic doses of ketamine, a non-competitive N-methyl-D-aspartate receptor antagonist2,3, provide rapid and long-lasting antidepressant effects in these patients4-6, but the molecular mechanism of these effects remains unclear7,8. Ketamine has been proposed to exert its antidepressant effects through its metabolite (2R,6R)-hydroxynorketamine ((2R,6R)-HNK)9. The antidepressant effects of ketamine and (2R,6R)-HNK in rodents require activation of the mTORC1 kinase10,11. mTORC1 controls various neuronal functions12, particularly through cap-dependent initiation of mRNA translation via the phosphorylation and inactivation of eukaryotic initiation factor 4E-binding proteins (4E-BPs)13. Here we show that 4E-BP1 and 4E-BP2 are key effectors of the antidepressant activity of ketamine and (2R,6R)-HNK, and that ketamine-induced hippocampal synaptic plasticity depends on 4E-BP2 and, to a lesser extent, 4E-BP1. It has been hypothesized that ketamine activates mTORC1-4E-BP signalling in pyramidal excitatory cells of the cortex8,14. To test this hypothesis, we studied the behavioural response to ketamine and (2R,6R)-HNK in mice lacking 4E-BPs in either excitatory or inhibitory neurons. The antidepressant activity of the drugs is mediated by 4E-BP2 in excitatory neurons, and 4E-BP1 and 4E-BP2 in inhibitory neurons. Notably, genetic deletion of 4E-BP2 in inhibitory neurons induced a reduction in baseline immobility in the forced swim test, mimicking an antidepressant effect. Deletion of 4E-BP2 specifically in inhibitory neurons also prevented the ketamine-induced increase in hippocampal excitatory neurotransmission, and this effect concurred with the inability of ketamine to induce a long-lasting decrease in inhibitory neurotransmission. Overall, our data show that 4E-BPs are central to the antidepressant activity of ketamine.

The effect of fluid overload in the presence of an epidural on the strength of colonic anastomoses.

BACKGROUND: Despite the beneficial effects of epidurals in intra-abdominal surgery, the incidence of anastomotic leak remains controversial when used. Moreover, studies have also shown that fluid overload may be deleterious to anastomoses. The purpose of this paper is to evaluate the effects of varying intraoperative fluid protocols, in the presence of an epidural, on the burst pressure strength of colonic anastomoses. METHODS: An epidural was installed in 18 rabbits, divided into three groups. Group 1 received 30 mL/kg/h Ringer's lactate, Group 2 received 100 mL/kg/h Ringer's lactate, and Group 3 received 30 mL/kg/h Pentaspan. Two colo-colonic anastomoses were performed per rabbit. On postoperative day 7 the anastomoses were resected and their burst pressures measured as a surrogate for anastomotic leak. RESULTS: When comparing the average burst pressures of all three groups, there was a significant difference (P = 0.04). The anastomoses in the 100 mL/kg/h Ringer's lactate group were shown to be the weakest, with 64% of the anastomoses having burst under 120 mm Hg. The rabbits hydrated with Pentaspan had the highest strength, with no anastomoses bursting under 120 mm Hg. This translated into significant burst pressure differences (P = 0.02) between Group 2 and Group 3. CONCLUSION: These results suggest that fluid overload with a crystalloid, in the presence of an epidural, may be deleterious to the healing of colonic anastomoses, creating a higher risk of anastomotic leak. Intraoperative resuscitation should thus focus on goal-directed euvolemia with appropriate amounts of colloids and/or crystalloids to prevent the risk of weakening anastomoses, especially in patients with epidurals.

Sex differences in developmental patterns of neocortical astroglia: A mouse translatome database.

Astroglial cells are key players in the development and maintenance of neurons and neuronal networks. Astroglia express steroid hormone receptors and show rapid responses to hormonal manipulations. However, despite important sex differences in the cortex and hippocampus, few studies have examined sex differences in astroglial cells in telencephalic development. To characterize the cortical astroglial translatome in male and female mice across postnatal development, we use translating ribosome affinity purification together with RNA sequencing and immunohistochemistry to phenotype astroglia at six developmental time points. Overall, we find two distinct astroglial phenotypes between early (P1-P7) and late development (P14-adult), independent of sex. We also find sex differences in gene expression patterns across development that peak at P7 and appear to result from males reaching a mature astroglial phenotype earlier than females. These developmental sex differences could have an impact on the construction of neuronal networks and windows of vulnerability to perturbations and disease.

Differential Effects of Short-term Environmental Enrichment in Juvenile and Adult Mice.

Environmental enrichment has been shown to increase cognitive abilities and accelerate recovery from a number of disease states. Typically, enrichment protocols last from four to eight weeks, however, it has previously been shown that two weeks of environmental enrichment is sufficient to increase cognitive abilities and the proliferation of the astroglial stem cell pool in juvenile mice. The current study examines whether a short-term enrichment protocol can induce similar effects in adults as compared to juveniles. Using juvenile and adult wild-type mice, we examined the effects of short-term environmental enrichment (including a running wheel) on cognitive abilities, anxiety-like behaviour, and the stem cell potential of sub-ventricular neural stem cells (NSC's) in vitro using neurosphere assays. We found that short-term environmental enrichment decreased anxiety behaviour and increased overall memory abilities similarly in juveniles and adults. However, the rate of acquisition on the Morris water maze, hippocampal Sox2 and Ki67 expression, and neurosphere potential increased in response to enrichment only in juveniles, suggesting that the effects of enrichment on these measures are age dependant. Together, these data suggest that the potential beneficial effects of environmental manipulations decrease with age.

A Further Analysis and Commentary on: Profiling Changes in Cortical Astroglial Cells Following Chronic Stress.

The neuroplasticity hypothesis of depression proposes that major depressive disorders are related to decreased hippocampal and cortical neural plasticity, which is reversed by antidepressant treatment. Astroglial cells have emerged as key mediators of neural plasticity and are involved in the cause and treatment of depression and anxiety-like behaviors. One of the ways that astroglia modulate neuroplasticity is through the formation and maintenance of perineuronal nets (PNNs). Perineuronal nets are important extracellular matrix components that respond to stress and are implicated in anxiety-like behaviors. Normally, astroglial cells continuously turnover PNNs by degrading and donating PNN proteins; however, chronic stress slows PNN protein degradation and increases cortical PNN expression overall. In this report, we used weighted gene co-expression network analysis and eigengene analysis to further delineate the pathways and key regulators involved in the astroglial-PNN relationship following chronic stress. Our analyses indicate that chronic variable stress induces the expression of PNNs through inhibition of trophic pathways and key transcription factors in astroglial cells. These data further support the integral role of astroglial cells in the neuroplasticity hypothesis of depression through their modulation of anxiety-like behaviors and PNNs.

Fibroblast growth factor 2 is necessary for the antidepressant effects of fluoxetine.

Previous research has shown that fibroblast growth factor 2 protein (FGF2) can act as an anxiolytic and anti-depressive agent in rodents. Levels of hippocampal FGF2 and FGF2 receptors are decreased in post-mortem brains of individuals with mood disorders. No changes in FGF2 were noted in the post-mortem brains of individuals with mood disorders that were successfully treated with anti-depressant medication prior to death. Mutations in the FGF2 gene in humans have been shown to predict non-responsiveness to the therapeutic effects of selective serotonin reuptake inhibitors (SSRIs). These findings suggest that FGF2 may potentially be a target of and/or required for the therapeutic effects of antidepressant medications. To test this, we employed a rodent model of depressive behaviour, chronic variable stress (CVS) in conjunction with antidepressant treatment (fluoxetine) in wild-type (WT) and FGF2 knockout mice (FGF2KO) and examined depressive and anxiety behaviors. Results showed that fluoxetine reversed the effects of CVS on depressive and anxiety behaviours in wild-type mice only, suggesting that the FGF2 gene is indeed necessary for the therapeutic effects of fluoxetine. Interestingly, CVS decreased hippocampal FGF2 levels and fluoxetine partially reversed this effect. Because FGF2 has been previously shown to modify HPA activity through hippocampal glucocorticoid receptors (GR), we examined levels of glucocorticoid receptors and found a decrease in GR in response to CVS, with a further decrease in FGF2KO. No effect of fluoxetine on GR was observed in either WT or FGF2KO mice. This suggests that further changes in glucocorticoid receptors are not necessary for the anti-depressant effects of fluoxetine in WT mice, although decreased glucocorticoid receptors in response to FGF2 deletion may preclude the therapeutic actions of fluoxetine in FGF2KO. Whether astroglia, astroglial functions, or HPA changes are the downstream target of FGF2-mediated changes induced by fluoxetine remains to be determined, however, the current study reaffirms the potential of FGF2 as a novel therapeutic target in the treatment of depression and anxiety disorders.

Profiling changes in cortical astroglial cells following chronic stress.

Recent studies have suggested that cortical astroglia play an important role in depressive-like behaviors. Potential astroglial contributions have been proposed based on their known neuroplastic functions, such as glutamate recycling and synaptic plasticity. However, the specific mechanisms by which astroglial cells may contribute or protect against a depressive phenotype remain unknown. To delineate astroglial changes that accompany depressive-like behavior, we used astroglial-specific bacTRAP mice exposed to chronic variable stress (CVS) and profiled the astroglial translatome using translating ribosome affinity purification (TRAP) in conjunction with RNAseq. As expected, CVS significantly increased anxiety- and depressive-like behaviors and corticosterone levels and decreased GFAP expression in astroglia, although this did not reflect a change in the total number of astroglial cells. TRAPseq results showed that CVS decreased genes associated with astroglial plasticity: RhoGTPases, growth factor signaling, and transcription regulation, and increased genes associated with the formation of extracellular matrices such as perineuronal nets (PNNs). PNNs inhibit neuroplasticity and astroglia contribute to the formation, organization, and maintenance of PNNs. To validate our TRAPseq findings, we showed an increase in PNNs following CVS. Degradation of PNNs in the prefrontal cortex of mice exposed to CVS reversed the CVS-induced behavioral phenotype in the forced swim test. These data lend further support to the neuroplasticity hypothesis of depressive behaviors and, in particular, extend this hypothesis beyond neuronal plasticity to include an overall decrease in genes associated with cortical astroglial plasticity following CVS. Further studies will be needed to assess the antidepressant potential of directly targeting astroglial cell function in models of depression.

Merging evidence-based psychosocial interventions in schizophrenia.

Psychosocial interventions are an essential part of the treatment for people with severe mental illness such as schizophrenia. The criteria regarding what makes an intervention "evidence-based" along with a current list of evidence-based interventions are presented. Although many evidence-based interventions exist, implementation studies reveal that few, if any, are ever implemented in a given setting. Various theories and approaches have been developed to better understand and overcome implementation obstacles. Among these, merging two evidence-based interventions, or offering an evidence-based intervention within an evidence-based service, are increasingly being reported and studied in the literature. Five such merges are presented, along with their empirical support: cognitive behavior therapy (CBT) with skills training; CBT and family psychoeducation; supported employment (SE) and skills training; SE and cognitive remediation; and SE and CBT.