Neural plasticity and proliferation in the generation of antidepressant effects: hippocampal implication

It is widely accepted that changes underlying depression and antidepressant-like effects involve not only alterations in the levels of neurotransmitters as monoamines and their receptors in the brain, but also structural and functional changes far beyond. During the last two decades, emerging theories are providing new explanations about the neurobiology of depression and the mechanism of action of antidepressant strategies based on cellular changes at the CNS level. The neurotrophic/plasticity hypothesis of depression, proposed more than a decade ago, is now supported by multiple basic and clinical studies focused on the role of intracellular-signalling cascades that govern neural proliferation and plasticity. Herein, we review the state-of-the-art of the changes in these signalling pathways which appear to underlie both depressive disorders and antidepressant actions. We will especially focus on the hippocampal cellularity and plasticity modulation by serotonin, trophic factors as brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF) through intracellular signalling pathways-cAMP, Wnt/ β -catenin, and mTOR. Connecting the classic monoaminergic hypothesis with proliferation/neuroplasticity-related evidence is an appealing and comprehensive attempt for improving our knowledge about the neurobiological events leading to depression and associated to antidepressant therapies

Experiencia COIL en el Grado en Enfermería. Percepción de los estudiantes

[ES] Objetivo: Realizar una experiencia intercultural remota entre los estudiantes de enfermería de la Universidad de Washington y de León centrada en el abordaje de contenidos relacionados con la salud mental. Co-aprender sobre los sistemas de salud de Estados Unidos y de España, centrándose específicamente en el abordaje de la salud mental en los distintos países. Conocer la percepción de los estudiantes tras realizar la experiencia innovadora. Descripción de la innovación: Se lleva a cabo un proyecto de innovación docente siguiendo la metodología COIL durante el segundo semestre del curso académico 2021/2022 entre los estudiantes de la Universidad de Washington y de la Universidad de León del grado en enfermería. Esta experiencia siguió la metodología COIL. Principales resultados: Los estudiantes, obtuvieron la máxima calificación posible en las entregas de los trabajos. Las expectativas tras la realización de esta actividad son elevadas y manifiestan utilidad en esta experiencia dentro de la asignatura y para su futuro desarrollo profesional. Conclusiones: El aprendizaje internacional colaborativo en línea es un método innovador que ofrece a los estudiantes de enfermería la oportunidad de desarrollar conciencia intercultural, necesaria en su formación y en su futura práctica como enfermeros. Los estudiantes señalan un beneficio a la hora de atender a pacientes con problemas de salud mental tras la realización de esta experiencia de innovación

Differential mRNA expression of neuroproliferative/neuroplastic transcription factors induced by venlafaxine and RS67333 assessed in organotypic hippocampal slice cultures

Resumen del trabajo presentado al: "6th European Congress of Pharmacolgy" celebrado en Granada del 17 al 20 de julio de 2012.Supported by: Ministerio de Ciencia e Innovación (SAF07-61862; SA F2011-25020).Peer Reviewe

Dose- and time-dependent modulation of mRNA expression of neuroproliferative/neuroplastic transcription factors in organotypic hippocampal slice cultures by selective and non-selctive serotonin reuptake inhibitors

Recent data suggest the involvement of neuroproliferative/neuroplastic signalling pathways in the mechanisms of the antidepressant action. The real implication of such process in the onset or in the efficacy profile of the antidepressants has not been yet elucidated. The objective of the present study was to analyze, by real time PCR, the dose dependence and the time course of the expression of plasticityrelated genes induced by both paroxetine (selective 5-HT reuptake inhibitor, SSRI), and venlafaxine (a serotonin-norepinephrine reuptake inhibitor, SNRI) in organotypic hippocampal slice cultures obtained from P7 Sprague Dawley male rats. In each experiment, slices from 4 animals were pooled and used to evaluate the effect of each drug. The slices were exposed to 1uM and 10uM of either paroxetine or venlafaxine dissolved in culture medium for 1, 3 or 7 days. We tested mRNA levels of Wnt/ß-catenin pathway related genes: ß-catenin gene (Ctnnb1), Axin1, Axin2, Myc, as well as Wnt/ß-catenin-nonrelated genes: Notch1 and Ccnd1. Relative expression levels were expressed as fold of change using the 2-ΔΔCt method with GAPDH as internal reference. ANOVA analysis showed a dose- and time-dependent significant effect of venlafaxine and paroxetine treatment. Treatment with 1 uM venlafaxine increased mRNA expression of Ccnd1 (F:24.6;p<0.001 for 1 and 7 days) and Notch1 (F:278.5;p<0.001 for 1 and 7 days), but not Wnt/ß-catenin related genes. 1 uM paroxetine increased expression of both, Wnt/ß-catenin related genes such as: Ctnnb1 (F:10.0;p<0.05 for 3 and 7 days), Axin1 (F:136.4;p<0.05 for 1, 3 and 7 days); Axin2 (F:158.2;p<0.05 for 1, 3 and 7 days), Myc (F:113.6;p<0.001 for 1 and 3 days), and Ccnd1 (F:361.9; p<0.001 for 1 and 7 days) but not in Notch1 expression. Both venlafaxine and paroxetine (10 uM) induced a significant decrease for Wnt/ß-catenin related and unrelated genes as Ctnnb1 (F:180.6 and F:25.5;p<0.001 and p<0.01 respectively at 3 and 7 days), Axin1 (F:325.2 and F:24.5;p<0.001 and p<0.01 respectively at 1, 3 and 7 days), Axin2 (F:38.04 and F:19.68;p<0.001 and p<0.001 respectively at 1, 3 and 7 days), Myc (F:231.9 and F:129.4;p<0.001 and p<0.001 respectively at 1, 3 and 7 days), Notch1 (F:421.1 and F:122.7;p<0.001 respectively at 1, 3 and 7 days) and Ccnd1 (F:351.1 and F:30.1;p<0.001respectively at 1 and 7 days). Our results on mRNA levels of neuroplastic/neuroproliferative genes show a different pattern for dose-dependent gene expression between SSRI and SNRI antidepressants on factors involved in the proliferation and maintenance of neural stem/progenitor cells, which could reflect differences in the antidepressant profile of these drugs.Supported: Ministerio de Ciencia e Innovación (SAF07-61862;SAF2011-25020).Peer Reviewe

Time course of transcription factors mRNA in organotypic hippocampal slice cultures after exposure to RS67333, a putative faster-acting antidepressant drugs

Trabajo presentado al: "8th Fens Forum of Neuroscience" celebrado en Barcelon del 14 al 18 de julio de 2012.It has been recently suggested that RS67333, a 5-HT4 receptor agonist, induces both, antidepressant-like responses and neuroplasticity-associated changes with a short onset of action (3-7 days), suggesting a new strategy for developing faster-acting antidepressant drugs. In the adult mammalian brain, neural progenitors progress through distinct stages to become mature neurons, this progression being tightly controlled by cell-cell interactions and signals in the neurogenic niche. However, less is known about the role of antidepressant drugs in that signaling modulation. The objective of the present work was to analyze, by QRT-PCR, the time-course of the changes induced by RS67333 on the expression of plasticity-related genes mRNA in organotypic hippocampal slice cultures of P7 rats. The slices were exposed to 10 mM RS67333 for 1, 3, 5 or 7 days. We tested mRNA levels of ß-catenin gene (Ctnnb1), Wnt/ß-catenin target genes: Axin1, Axin2, c-Myc, Ccnd1, as well as ß-catenin-nonrelated genes: c-jun, Notch and Vegfa. Relative expression levels were calculated with GAPDH as internal reference, using the 2ΔΔ Ct method and expressed as fold of change. All tested genes were upregulated by RS67333 exposition. The higher increase was found after 3 days of drug exposition for Ctnnb1 (6.45±0.66;p< 0.001), Axin1 (4.32±0.03;p< 0.001), Axin2 (4.52±0.08;p< 0.001), c-jun (10.58±1.87;p< 0.001), c-myc (7.22±1.29;p< 0.001); Ccnd 1 (16.10±0.22;p< 0.001) Notch (10.21±0.66;p< 0.001) and Vegfa (4.03±0.28;p< 0.001). The mRNA levels were reduced after longer RS67333 exposition, but a significant increase of mRNA levels for Axin1 (1.57±0.09), Axin2 (1.26±0.07), c-jun (7.22±1.28) Notch (1.59±0.03) and Vegfa (2.75±0.19) was still found after 7 days of RS67333 exposition. Our results show that RS67333 induces an increase in mRNA expression of neuroplasticityrelated factors as well as factors involved in the maintenance of neural stem/progenitor cells. This modulation could be mediating the faster antidepressant responses of this drug.Supported: Ministerio de Ciencia e Innovación (SAF07-61862;SAF2011-25020).Peer Reviewe

Unfolded protein response to global ischemia following 48 h of reperfusion in the rat brain: the effect of age and meloxicam

[EN] The unfolded protein response (UPR) in the hippocampal regions Cornu Ammonis 1 hippocampal region, Cornu Ammonis 3 hippocampal region, and dentate gyrus, as well as in the cerebral cortex of 3-month-old and 18-month-old rats were studied in a model of 15 min of global cerebral ischemia followed by 48 h of reperfusion. UPR was measured by quantifying the protein disulfide isomerase (PDI), C/EBP-homologous protein (CHOP), GRP78 and GRP94 transcripts using qPCR and the amounts of PDI and GRP78 by western blot. The study shows how the mRNA levels of these genes were similar in 3-month-old and 18-month-old sham-operated animals, but the ischemic insult elicited a noticeable increase in the expression of these genes in young animals that was scarcely appreciable in older animals. The striking increase in the mRNA levels of these genes in 3-month-old animals was abolished or even reverted by treatment with meloxicam, an anti-inflammatory agent. Western blot assays showed that the UPR was still detectable 48 h after ischemia in some of the studied areas, and provided evidence that the UPR is different between young and older animals. Western blot assays carried out in young animals also showed that meloxicam elicited different effects on the levels of PDI and GRP78 in the cerebral cortex and the hippocampus. We conclude that the UPR response to ischemic/reperfusion insult is age- and probably inflammation-dependent and could play an important role in ischemic vulnerability. The UPR appears to be strongly decreased in aged animals, suggesting a reduced ability for cell survival.SIJunta de Castilla y León.University of Leo

Differential effect of transient global ischaemia on the levels of GABA(A) receptor subunit mRNAs in young and older rats.

Aims: This study has investigated how global brain ischaemia/reperfusion (I/R) modifies levels of mRNAs encoding GABA(A) receptor alpha1, beta2 and gamma2 subunits and glutamic acid decarboxylase 65 (GAD65) in an age- and structure-dependent manner. Gene expression in response to treatment with the anti-inflammatory agent meloxicam was also investigated. Methods: Global ischaemia was induced in 3- and 18-month-old male Sprague-Dawley rats. CA1, CA3, and dentate gyrus (DG) hippocampal areas, cerebral cortex (CC) and caudate putamen (C-Pu) from sham-operated and I/R-injured animals were excised 48 h after the insult and prepared for quantitative polymerase chain reaction (qPCR) assays. Following I/R, meloxicam treatment was also carried out on young animals. Results: Data revealed significant decreases in the levels of all GABA(A) receptor subunit transcripts in the hippocampus of both young and older injured animals compared to sham-operated ones. In contrast, there was either an increase or no change in GAD65 mRNA levels. GABA(A) receptor subunit transcript decreases were also observed in the CC and C-Pu in young injured animals but not in the CC of the older injured ones; interestingly, significant increases were observed in the C-Pu of older injured animals compared to controls. Meloxicam treatment following the insult resulted in a diminution of the previously-described I/R response. Conclusions: The data indicate that I/R results in the modification of the levels of several gene transcripts involved in GABAergic signalling in both the pre- and postsynaptic components, of this neurotransmitter system, in an age- and structure-dependent manner