RESUMEN
St. John's wort is an herb, long used in folk medicine for the treatment of mild depression. Its antidepressant constituent, hyperforin, has properties such as chemical instability and induction of drug-drug interactions that preclude its use for individual pharmacotherapies. Here we identify the transient receptor potential canonical 6 channel (TRPC6) as a druggable target to control anxious and depressive behavior and as a requirement for hyperforin antidepressant action. We demonstrate that TRPC6 deficiency in mice not only results in anxious and depressive behavior, but also reduces excitability of hippocampal CA1 pyramidal neurons and dentate gyrus granule cells. Using electrophysiology and targeted mutagenesis, we show that hyperforin activates the channel via a specific binding motif at TRPC6. We performed an analysis of hyperforin action to develop a new antidepressant drug that uses the same TRPC6 target mechanism for its antidepressant action. We synthesized the hyperforin analog Hyp13, which shows similar binding to TRPC6 and recapitulates TRPC6-dependent anxiolytic and antidepressant effects in mice. Hyp13 does not activate pregnan-X-receptor (PXR) and thereby loses the potential to induce drug-drug interactions. This may provide a new approach to develop better treatments for depression, since depression remains one of the most treatment-resistant mental disorders, warranting the development of effective drugs based on naturally occurring compounds.
Asunto(s)
Antidepresivos , Hypericum , Floroglucinol , Canal Catiónico TRPC6 , Terpenos , Animales , Ratones , Antidepresivos/aislamiento & purificación , Antidepresivos/farmacología , Hypericum/química , Canal Catiónico TRPC6/agonistas , Canal Catiónico TRPC6/química , Floroglucinol/aislamiento & purificación , Floroglucinol/farmacología , Terpenos/aislamiento & purificación , Terpenos/farmacologíaRESUMEN
OBJECTIVE: The suggested link between major depression disorder (MDD) and blood-brain barrier (BBB) alterations supports an impact on the neurovascular unit in this disease condition. Here we investigate how pericytes, a major component in the neurovascular unit, respond to stress, stress hormones, proinflammatory cytokine and depression. METHOD: Hippocampal sections of chronic unpredictable stressed (CMS) rats, MDD patients and respective controls were immuno-stained against NG2, where the number of NG2+ pericytes in the molecular layer was counted. Proliferation of cultured pericytes after treatment with cortisol and IL-1ß was analyzed using radioactive-labeled thymidine. FINDINGS: The number of NG2+ pericytes was significantly higher in CMS animals than controls. Higher number of NG2+ pericytes was also detected in MDD patients, but the increase did not reach significance. IL-1ß, but not cortisol, induced a significant increase in proliferation of cultured pericytes. CONCLUSION: Our results indicate that exposure to stressful conditions affects the hippocampal pericyte population. These findings add to our knowledge about the impact of stress on the neurovascular unit, which might be relevant for understanding the alterations in BBB found in MDD patients.
Asunto(s)
Pericitos , Estrés Psicológico , Animales , Barrera Hematoencefálica , Citocinas , Hipocampo , Humanos , RatasRESUMEN
Stringent glucose demands render the brain susceptible to disturbances in the supply of this main source of energy, and chronic stress may constitute such a disruption. However, whether stress-associated cognitive impairments may arise from disturbed glucose regulation remains unclear. Here we show that chronic social defeat (CSD) stress in adult male mice induces hyperglycemia and directly affects spatial memory performance. Stressed mice developed hyperglycemia and impaired glucose metabolism peripherally as well as in the brain (demonstrated by PET and induced metabolic bioluminescence imaging), which was accompanied by hippocampus-related spatial memory impairments. Importantly, the cognitive and metabolic phenotype pertained to a subset of stressed mice and could be linked to early hyperglycemia 2 days post-CSD. Based on this criterion, â¼40% of the stressed mice had a high-glucose (glucose >150 mg/dL), stress-susceptible phenotype. The relevance of this biomarker emerges from the effects of the glucose-lowering sodium glucose cotransporter 2 inhibitor empagliflozin, because upon dietary treatment, mice identified as having high glucose demonstrated restored spatial memory and normalized glucose metabolism. Conversely, reducing glucose levels by empagliflozin in mice that did not display stress-induced hyperglycemia (resilient mice) impaired their default-intact spatial memory performance. We conclude that hyperglycemia developing early after chronic stress threatens long-term glucose homeostasis and causes spatial memory dysfunction. Our findings may explain the comorbidity between stress-related and metabolic disorders, such as depression and diabetes, and suggest that cognitive impairments in both types of disorders could originate from excessive cerebral glucose accumulation.
Asunto(s)
Conducta Animal/fisiología , Enfermedad Crónica/psicología , Hiperglucemia/fisiopatología , Trastornos de la Memoria/fisiopatología , Memoria Espacial/fisiología , Estrés Psicológico/fisiopatología , Animales , Conducta Animal/efectos de los fármacos , Compuestos de Bencidrilo/farmacología , Encéfalo/metabolismo , Encéfalo/fisiopatología , Enfermedad Crónica/tratamiento farmacológico , Glucosa/metabolismo , Glucósidos/farmacología , Hiperglucemia/tratamiento farmacológico , Hiperglucemia/metabolismo , Hiperglucemia/psicología , Masculino , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/psicología , Ratones , Ratones Endogámicos C57BL , Deseabilidad Social , Memoria Espacial/efectos de los fármacos , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/metabolismo , Estrés Psicológico/psicologíaRESUMEN
Brain energy metabolism actively regulates synaptic transmission and activity. We have previously shown that acute footshock (FS)-stress induces fast and long-lasting functional and morphological changes at excitatory synapses in prefrontal cortex (PFC). Here, we asked whether FS-stress increased energy metabolism in PFC, and modified related cognitive functions. Using positron emission tomography (PET), we found that FS-stress induced a redistribution of glucose metabolism in the brain, with relative decrease of [18F]FDG uptake in ventro-caudal regions and increase in dorso-rostral ones. Absolute [18F]FDG uptake was inversely correlated with serum corticosterone. Increased specific hexokinase activity was also measured in purified PFC synaptosomes (but not in total extract) of FS-stressed rats, which positively correlated with 2-Deoxy [3H] glucose uptake by synaptosomes. In line with increased synaptic energy demand, using an electron microscopy-based stereological approach, we found that acute stress induced a redistribution of mitochondria at excitatory synapses, together with an increase in their volume. The fast functional and metabolic activation of PFC induced by acute stress, was accompanied by rapid and sustained alterations of working memory performance in delayed response to T-maze test. Taken together, the present data suggest that acute stress increases energy consumption at PFC synaptic terminals and alters working memory.
Asunto(s)
Metabolismo Energético/fisiología , Memoria a Corto Plazo/fisiología , Corteza Prefrontal/metabolismo , Estrés Psicológico/metabolismo , Sinapsis/metabolismo , Animales , Masculino , Tomografía de Emisión de Positrones , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Rapid-acting antidepressants ketamine and (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) have overcome some of the major limitations of classical antidepressants. However, little is known about sex-specific differences in the behavioral and molecular effects of ketamine and (2R,6R)-HNK in rodents. METHODS: We treated mice with an intraperitoneal injection of either saline, ketamine (30 mg kg-1) or (2R,6R)-HNK (10 mg kg-1). We performed a comprehensive behavioral test battery to characterize the Arc-CreERT2 × CAG-Sun1/sfGFP mouse line which enables targeted recombination in active populations. We performed a molecular study in Arc-CreERT2 × CAG-Sun1/sfGFP female mice using both immunohistochemistry and in situ hybridization. RESULTS: Arc-CreERT2 × CAG-Sun1/sfGFP mice showed sex differences in sociability and anxiety tests. Moreover, ketamine and (2R,6R)-HNK had opposite effects in the forced swim test (FST) depending on gender. In addition, in male mice, ketamine-treated animals were less immobile compared to (2R,6R)-HNK, thus showing a different profile of the two drugs in the FST. At the molecular level we identified Bdnf mRNA level to be increased after ketamine treatment in female mice. CONCLUSION: Arc-CreERT2 × CAG-Sun1/sfGFP mice showed sex differences in social and anxiety behavior and a different pattern between ketamine and (2R,6R)-HNK in the FST in male and female mice. At the molecular level, female mice treated with ketamine showed an increase of Bdnf mRNA level, as previously observed in male mice.
Asunto(s)
Conducta Animal , Ketamina/análogos & derivados , Ketamina/administración & dosificación , Neuronas/metabolismo , Recombinación Genética , Caracteres Sexuales , Animales , Ansiedad/patología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Núcleo Celular/metabolismo , Modelos Animales de Enfermedad , Femenino , Proteínas Fluorescentes Verdes/metabolismo , Hipocampo/metabolismo , Masculino , Memoria Episódica , Ratones Transgénicos , Conducta SocialRESUMEN
Gender differences play a pivotal role in the pathophysiology and treatment of major depressive disorder. This is strongly supported by a mean 2:1 female-male ratio of depression consistently observed throughout studies in developed nations. Considering the urgent need to tailor individualized treatment strategies to fight depression more efficiently, a more precise understanding of gender-specific aspects in the pathophysiology and treatment of depressive disorders is fundamental. However, current treatment guidelines almost entirely neglect gender as a potentially relevant factor. Similarly, the vast majority of animal experiments analysing antidepressant treatment in rodent models exclusively uses male animals and does not consider gender-specific effects. Based on the growing interest in innovative and rapid-acting treatment approaches in depression, such as the administration of ketamine, its metabolites or electroconvulsive therapy, this review article summarizes the evidence supporting the importance of gender in modulating response to rapid acting antidepressant treatment. We provide an overview on the current state of knowledge and propose a framework for rodent experiments to ultimately decode gender-dependent differences in molecular and behavioural mechanisms involved in shaping treatment response.
Asunto(s)
Antidepresivos/farmacología , Animales , Antidepresivos/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/genética , Terapia Electroconvulsiva , Femenino , Humanos , Ketamina/metabolismo , Masculino , Resultado del TratamientoRESUMEN
Stressful events are associated with increased risk of mood disorders. Volumetric reductions have been reported in brain areas critical for the stress response, such as medial prefrontal cortex (mPFC), and dendritic remodeling has been proposed as an underlying factor. Here, we investigated the time-dependent effects of acute stress on dendritic remodeling within the prelimbic (PL) region of the PFC, and whether treatment with the antidepressant desipramine (DMI) may interfere. Rodents were subjected to foot-shock stress: dendritic length and spine density were analyzed 1 day, 7 days, and 14 days after stress. Acute stress produced increased spine density and decreased cofilin phosphorylation at 1 day, paralleled with dendritic retraction. An overall shift in spine population was observed at 1 day, resulting in a stress-induced increase in small spines. Significant atrophy of apical dendrites was observed at 1 day, which was prevented by chronic DMI, and at 14 days after stress exposure. Chronic DMI resulted in dendritic elaboration at 7 days but did not prevent the effects of FS-stress. Collectively, these data demonstrate that 1) acute stressors may induce rapid and sustained changes of PL neurons; and 2) chronic DMI may protect neurons from rapid stress-induced synaptic changes.
Asunto(s)
Antidepresivos Tricíclicos/farmacología , Dendritas/patología , Desipramina/farmacología , Plasticidad Neuronal/fisiología , Corteza Prefrontal/patología , Estrés Psicológico/patología , Factores Despolimerizantes de la Actina/metabolismo , Animales , Atrofia , Peso Corporal , Corticosterona/sangre , Dendritas/efectos de los fármacos , Dendritas/fisiología , Electrochoque , Pie , Masculino , Plasticidad Neuronal/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/fisiopatología , Células Piramidales/efectos de los fármacos , Células Piramidales/patología , Células Piramidales/fisiología , ARN Mensajero/metabolismo , Ratas Sprague-Dawley , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/fisiopatología , Factores de TiempoRESUMEN
Glutamatergic abnormalities have recently been implicated in the pathophysiology of depression, and the ionotropic glutamate receptors in particular have been suggested as possible underlying molecular determinants. The Flinders Sensitive Line (FSL) rats constitute a validated model of depression with dysfunctional regulation of glutamate transmission relatively to their control strain Flinders Resistant Line (FRL). To gain insight into how signaling through glutamate receptors may be altered in the FSL rats, we investigated the expression and phosphorylation of AMPA and NMDA receptor subunits in an enriched postsynaptic fraction of the hippocampus and prefrontal cortex. Compared to the hippocampal postsynaptic fractions of FRL rats, FSL rats exhibited decreased and increased levels of the NMDA receptor subunits GluN2A and GluN2B, respectively, causing a lower ratio of GluN2A/GluN2B. The GluA2/GluA3 AMPA receptor subunit ratio was significantly decreased while the expression of the individual GluA1, GluA2, and GluA3 subunits were unaltered including phosphorylation levels of GluA1 at S831 and S845. There were no changes in the prefrontal cortex. These results support altered expression of postsynaptic glutamate receptors in the hippocampus of FSL rats, which may contribute to the depressive-like phenotype of these rats.
Asunto(s)
Depresión/metabolismo , Hipocampo/metabolismo , Corteza Prefrontal/metabolismo , Receptores AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Depresión/genética , Subunidades de Proteína/genética , Subunidades de Proteína/metabolismo , Ratas , Receptores AMPA/genética , Receptores de N-Metil-D-Aspartato/genéticaRESUMEN
BACKGROUND: The novel antidepressant agomelatine, a melatonergic MT1/MT2 agonist combined with 5-HT2c serotonin antagonist properties, showed antidepressant action in preclinical and clinical studies. There is a general agreement that the therapeutic action of antidepressants needs the activation of slow-onset adaptations in downstream signalling pathways finally regulating neuroplasticity. In the last several years, particular attention was given to cAMP-responsive element binding protein (CREB)-related pathways, since it was shown that chronic antidepressants increase CREB phosphorylation and transcriptional activity, through the activation of calcium/calmodulin-dependent (CaM) and mitogen activated protein kinase cascades (MAPK/Erk1/2). Aim of this work was to analyse possible effects of chronic agomelatine on time-dependent changes of different intracellular signalling pathways in hippocampus and prefrontal/frontal cortex of male rats. To this end, measurements were performed 1 h or 16 h after the last agomelatine or vehicle injection. RESULTS: We have found that in naïve rats chronic agomelatine, contrary to traditional antidepressants, did not increase CREB phosphorylation, but modulates the time-dependent regulation of MAPK/Erk1/2 and Akt/glycogen synthase kinase-3 (GSK-3) pathways. CONCLUSION: Our results suggest that the intracellular molecular mechanisms modulated by chronic agomelatine may be partly different from those of traditional antidepressants and involve the time-dependent regulation of MAPK/Erk1/2 and Akt/GSK-3 signalling pathways. This could exert a role in the antidepressant efficacy of the drug.
Asunto(s)
Acetamidas/farmacología , Antidepresivos/farmacología , Lóbulo Frontal/efectos de los fármacos , Glucógeno Sintasa Quinasa 3/metabolismo , Hipocampo/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Animales , Western Blotting , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Lóbulo Frontal/enzimología , Hipocampo/enzimología , Masculino , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Distribución Aleatoria , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
BACKGROUND: Although a clear negative influence of chronic exposure to stressful experiences has been repeatedly demonstrated, the outcome of acute stress on key brain regions has only just started to be elucidated. Although it has been proposed that acute stress may produce enhancement of brain plasticity and that antidepressants may prevent such changes, we still lack ultrastructural evidence that acute stress-induced changes in neurotransmitter physiology are coupled with structural synaptic modifications. METHODS: Rats were pretreated chronically (14 days) with desipramine (10mg/kg) and then subjected to acute foot-shock stress. By means of serial section electron microscopy, the structural remodeling of medial prefrontal cortex glutamate synapses was assessed soon after acute stressor cessation and stress hormone levels were measured. RESULTS: Foot-shock stress induced a remarkable increase in the number of docked vesicles and small excitatory synapses, partially and strongly prevented by desipramine pretreatment, respectively. Acute stress-induced corticosterone elevation was not affected by drug treatment. CONCLUSIONS: Since desipramine pretreatment prevented the stress-induced structural plasticity but not the hormone level increase, we hypothesize that the preventing action of desipramine is located on pathways downstream of this process and/or other pathways. Moreover, because enhancement of glutamate system remodeling may contribute to overexcitation dysfunctions, this aspect could represent a crucial component in the pathophysiology of stress-related disorders.
Asunto(s)
Antidepresivos Tricíclicos/uso terapéutico , Desipramina/uso terapéutico , Ácido Glutámico/metabolismo , Corteza Prefrontal , Estrés Psicológico/patología , Estrés Psicológico/prevención & control , Vesículas Sinápticas/metabolismo , Animales , Corticosterona/sangre , Modelos Animales de Enfermedad , Electrochoque/efectos adversos , Masculino , Microscopía Electrónica de Transmisión , Modelos Neurológicos , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Corteza Prefrontal/patología , Ratas , Ratas Sprague-Dawley , Estrés Psicológico/sangre , Estrés Psicológico/etiología , Sinapsis/efectos de los fármacos , Sinapsis/fisiología , Sinapsis/ultraestructura , Vesículas Sinápticas/efectos de los fármacos , Factores de Tiempo , Proteína 1 de Transporte Vesicular de Glutamato/metabolismoRESUMEN
BACKGROUND: Growing compelling evidence from clinical and preclinical studies has demonstrated the primary role of alterations of glutamatergic transmission in cortical and limbic areas in the pathophysiology of mood disorders. Chronic antidepressants have been shown to dampen endogenous glutamate release from rat hippocampal synaptic terminals and to prevent the marked increase of glutamate overflow induced by acute behavioral stress in frontal/prefrontal cortex. Agomelatine, a new antidepressant endowed with MT1/MT2 agonist and 5-HT2C serotonergic antagonist properties, has shown efficacy at both preclinical and clinical levels. RESULTS: Chronic treatment with agomelatine, or with the reference drug venlafaxine, induced a marked decrease of depolarization-evoked endogenous glutamate release from purified hippocampal synaptic terminals in superfusion. No changes were observed in GABA release. This effect was accompanied by reduced accumulation of SNARE protein complexes, the key molecular effector of vesicle docking, priming and fusion at presynaptic membranes. CONCLUSIONS: Our data suggest that the novel antidepressant agomelatine share with other classes of antidepressants the ability to modulate glutamatergic transmission in hippocampus. Its action seems to be mediated by molecular mechanisms located on the presynaptic membrane and related with the size of the vesicle pool ready for release.
Asunto(s)
Acetamidas/farmacología , Antidepresivos/farmacología , Ciclohexanoles/farmacología , Ácido Glutámico/metabolismo , Hipocampo/citología , Sinaptosomas/efectos de los fármacos , Análisis de Varianza , Animales , Ionóforos de Calcio/farmacología , Ionomicina/farmacología , Masculino , Cloruro de Potasio/farmacología , Ratas , Ratas Sprague-Dawley , Proteínas SNARE/metabolismo , Sintaxina 1/metabolismo , Clorhidrato de Venlafaxina , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Chronic stress has the potential to impair health and may increase the vulnerability for psychiatric disorders. Emerging evidence suggests that specific neurometabolic dysfunctions play a role herein. In mice, chronic social defeat (CSD) stress reduces cerebral glucose uptake despite hyperglycemia. We hypothesized that this metabolic decoupling would be reflected by changes in contact sites between mitochondria and the endoplasmic reticulum, important intracellular nutrient sensors, and signaling hubs. We thus analyzed the proteome of their biochemical counterparts, mitochondria-associated membranes (MAMs) from whole brain tissue obtained from CSD and control mice. This revealed a lack of the glucose-metabolizing enzyme hexokinase 3 (HK3) in MAMs from CSD mice. In controls, HK3 protein abundance in MAMs and also in striatal synaptosomes correlated positively with peripheral blood glucose levels, but this connection was lost in CSD. We conclude that the ability of HK3 to traffic to sites of need, such as MAMs or synapses, is abolished upon CSD and surmise that this contributes to a cellular dysfunction instigated by chronic stress. KEY MESSAGES : Chronic social defeat (CSD) alters brain glucose metabolism CSD depletes hexokinase 3 (HK3) from mitochondria-associated membranes (MAMs) CSD results in loss of positive correlation between blood glucose and HK3 in MAMs and synaptosomes.
Asunto(s)
Glucemia , Hexoquinasa , Animales , Glucemia/metabolismo , Encéfalo/metabolismo , Glucosa/metabolismo , Hexoquinasa/metabolismo , Humanos , Ratones , Membranas Mitocondriales/metabolismoRESUMEN
Major depressive disorder (MDD) is a highly heterogeneous disorder, which may partly explain why treatment outcome using antidepressants is unsatisfactory. We investigated the onset of depression as a possible clinical marker for therapy response prediction in the context of somatic biomarkers blood pressure and plasma electrolyte concentration. 889 MDD patients were divided into early (EO, n = 226), intermediate (IO, n = 493), and late onset (LO, n = 169) patients and were analyzed for differences in socio-demographic and clinical parameters, comorbidities and treatment outcome as well as systolic blood pressure and electrolytes. EO patients more often suffered from a recurrent depression, had more previous depressive episodes, a higher rate of comorbid axis I and II disorders, and more often reported of suicidality (p < 0.001) compared to IO and LO patients. Treatment outcome was not different from IO and LO patients, although LO patients responded faster. EO patients who showed an early non-improvement of depression after 2 weeks of therapy (<20% improvement) had a 4.3-fold higher likelihood to become non-remitter as compared to LO patients with an early improvement. EO patients had significantly lower systolic blood pressure than patients with IO or LO and electrolytes in EO patients were significantly correlated with depression severity. Our results confirm other studies showing an association of an early onset of depression with a slower treatment response. The worse treatment outcome in patients with an additional early non-improvement to antidepressant therapy opens perspectives to develop and test individualized treatment approaches for EO and LO patients in the future, which may be based on differences in autonomic regulation.
Asunto(s)
Trastorno Depresivo Mayor , Edad de Inicio , Antidepresivos/uso terapéutico , Depresión , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/epidemiología , Humanos , Resultado del TratamientoRESUMEN
SCOPE: Probiotics exert immunomodulatory effects and may influence tryptophan metabolism in the host. Deficiency of nutrients related to C1 metabolism might stimulate inflammation by enhancing the kynurenine pathway. This study used Sprague Dawley rats to investigate whether a methyl-deficient diet (MDD) may influence tryptophan/kynurenine pathways and cytokines and whether probiotics can mitigate these effects. METHODS AND RESULTS: Rats are fed a control or MDD diet. Animals on the MDD diet received vehicle, probiotics (L. helveticus R0052 and B. longum R0175), choline, or probiotics + choline for 10 weeks (n = 10 per group). Concentrations of plasma kynurenine metabolites and the methylation and inflammatory markers in plasma and liver are measured. RESULTS: MDD animals (vs controls) show upregulation of plasma kynurenine, kynurenic acid, xanthurenic acid, 3-hydroxyxanthranilic acid, quinolinic acid, nicotinic acid, and nicotinamide (all p < 0.05). In the MDD rats, the probiotics (vs vehicle) cause lower anthranilic acid and a trend towards lower kynurenic acid and picolinic acid. Compared to probiotics alone, probiotics + choline is associated with a reduced enrichment of the bacterial strains in cecum. The interventions have no effect on inflammatory markers. CONCLUSIONS: Probiotics counterbalance the effect of MDD diet and downregulate downstream metabolites of the kynurenine pathway.
Asunto(s)
Deficiencia de Colina/metabolismo , Quinurenina/metabolismo , Probióticos/farmacología , Animales , Colina/administración & dosificación , Deficiencia de Ácido Fólico/metabolismo , Masculino , Metionina/deficiencia , Metilación , Ratas , Ratas Sprague-Dawley , Triptófano/metabolismoRESUMEN
Major depressive disorder is the most prevalent mental illness worldwide, still its pharmacological treatment is limited by various challenges, such as the large heterogeneity in treatment response and the lack of insight into the neurobiological pathways underlying this phenomenon. To decode the molecular mechanisms shaping antidepressant response and to distinguish those from general paroxetine effects, we used a previously established approach targeting extremes (i.e., good vs poor responder mice). We focused on the dentate gyrus (DG), a subregion of major interest in the context of antidepressant mechanisms. Transcriptome profiling on micro-dissected DG granule cells was performed to (i) reveal cell-type-specific changes in paroxetine-induced gene expression (paroxetine vs vehicle) and (ii) to identify molecular signatures of treatment response within a cohort of paroxetine-treated animals. We identified 112 differentially expressed genes associated with paroxetine treatment. The extreme group comparison (good vs poor responder) yielded 211 differentially expressed genes. General paroxetine effects could be distinguished from treatment response-associated molecular signatures, with a differential gene expression overlap of only 4.6% (15 genes). Biological pathway enrichment and cluster analyses identified candidate mechanisms associated with good treatment response, e.g., neuropeptide signaling, synaptic transmission, calcium signaling, and regulation of glucocorticoid secretion. Finally, we examined glucocorticoid receptor (GR)-dependent regulation of selected response-associated genes to analyze a hypothesized interplay between GR signaling and good antidepressant treatment response. Among the most promising candidates, we suggest potential targets such as the developmental gene Otx2 or Htr2c for further investigations into antidepressant treatment response in the future.
Asunto(s)
Trastorno Depresivo Mayor , Animales , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Giro Dentado , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/genética , Hipocampo , Ratones , Paroxetina/farmacología , Paroxetina/uso terapéuticoRESUMEN
The precise mechanisms underlying the detrimental effects of early life adversity (ELA) on adult mental health remain still elusive. To date, most studies have exclusively targeted neuronal populations and not considered neuron-glia crosstalk as a crucially important element for the integrity of stress-related brain function. Here, we have investigated the impact of ELA, in the form of a limited bedding and nesting material (LBN) paradigm, on a glial subpopulation with unique properties in brain homeostasis, the NG2+ cells. First, we have established a link between maternal behavior, activation of the offspring's stress response and heterogeneity in the outcome to LBN manipulation. We further showed that LBN targets the hippocampal NG2+ transcriptome with glucocorticoids being an important mediator of the LBN-induced molecular changes. LBN altered the NG2+ transcriptome and these transcriptional effects were correlated with glucocorticoids levels. The functional relevance of one LBN-induced candidate gene, Scn7a, could be confirmed by an increase in the density of voltage-gated sodium (Nav) channel activated currents in hippocampal NG2+ cells. Scn7a remained upregulated until adulthood in LBN animals, which displayed impaired cognitive performance. Considering that Nav channels are important for NG2+ cell-to-neuron communication, our findings provide novel insights into the disruption of this process in LBN mice.
RESUMEN
Delayed onset of antidepressant action is a shortcoming in depression treatment. Ketamine and its metabolite (2R,6R)-hydroxynorketamine (HNK) have emerged as promising rapid-acting antidepressants. However, their mechanism of action remains unknown. In this study, we first described the anxious and depression-prone inbred mouse strain, DBA/2J, as an animal model to assess the antidepressant-like effects of ketamine and HNK in vivo. To decode the molecular mechanisms mediating HNK's rapid antidepressant effects, a longitudinal cerebrospinal fluid (CSF) proteome profiling of its acute and sustained effects was conducted using an unbiased, hypothesis-free mass spectrometry-based proteomics approach. A total of 387 proteins were identified, with a major implication of significantly differentially expressed proteins in the glucocorticoid receptor (GR) signaling pathway, providing evidence for a link between HNK and regulation of the stress hormone system. Mechanistically, we identified HNK to repress GR-mediated transcription and reduce hormonal sensitivity of GR in vitro. In addition, mammalian target of rapamycin (mTOR) and brain-derived neurotrophic factor (BDNF) were predicted to be important upstream regulators of HNK treatment. Our results contribute to precise understanding of the temporal dynamics and molecular targets underlying HNK's rapid antidepressant-like effects, which can be used as a benchmark for improved treatment strategies for depression in future.
RESUMEN
Stress plays a crucial role in the pathogenesis of psychiatric disorders and affects neuronal plasticity in different brain regions. We have previously found that acute foot-shock (FS) stress elicits fast and long-lasting functional and morphological remodeling of excitatory neurons in the prefrontal cortex (PFC), which were partly prevented by the pretreatment with antidepressants. Here we investigated, whether acute stress and pretreatment with desipramine (DMI) interfere in hippocampal dendritic remodeling. Male Sprague-Dawley rats were subjected to acute FS-stress, followed by measurement of time-dependent (1, 7 and 14â¯days) structural plasticity (dendritic arborization, spine number and morphology) in hippocampal CA1 pyramidal neurons and expression patterns of molecular markers implicated in neuronal plasticity. We found that acute stress significantly decreased spine number, dendritic length, and altered spine morphometric parameters at all time points evaluated after stress. This was paralleled by changes in the gene expression of Spinophilin and Cdc42, and protein expression of homer1. Pretreatment with DMI prevented the stress-induced dendritic atrophy and spine loss 14â¯days after acute FS. However, DMI treatment without stress differentially affected the expression patterns of spine-related genes and proteins. In conclusion, acute FS-stress and pretreatment with DMI significantly changed dendritic morphology, including number and morphology of spines, and the length of dendrites in hippocampal CA1 pyramidal cells as early as 1â¯day, and sustained up to 14â¯days after acute FS. The findings were paralleled by changes in gene and protein expression of actin binding and cytoskeletal proteins, Rho GTPases, and postsynaptic scaffolding proteins.
Asunto(s)
Hipocampo , Células Piramidales , Animales , Dendritas , Espinas Dendríticas , Masculino , Plasticidad Neuronal , Corteza Prefrontal , Ratas , Ratas Sprague-DawleyRESUMEN
When administered as a single subanesthetic dose, the N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine, produces rapid (within hours) and relatively sustained antidepressant actions even in treatment-resistant patients. Preclinical studies have shown that ketamine increases dendritic spine density and synaptic proteins in brain areas critical for the actions of antidepressants, yet the temporal relationship between structural changes and the onset of antidepressant action remains poorly understood. In this study, we examined the effects of a single dose of S-ketamine (15 mg/kg) on dendritic length, dendritic arborization, spine density, and spine morphology in the Flinders Sensitive and Flinders Resistant Line (FSL/FRL) rat model of depression. We found that already 1 h after injection with ketamine, apical dendritic spine deficits in CA1 pyramidal neurons of FSL rats were completely restored. Notably, the observed increase in spine density was attributable to regulation of both mushroom and long-thin spines. In contrast, ketamine had no effect on dendritic spine density in FRL rats. On the molecular level, ketamine normalized elevated levels of phospho-cofilin and the NMDA receptor subunits GluN2A and GluN2B and reversed homer3 deficiency in hippocampal synaptosomes of FSL rats. Taken together, our data suggest that rapid formation of new spines may provide an important structural substrate during the initial phase of ketamine's antidepressant action.