Depression-Associated Gene Negr1-Fgfr2 Pathway Is Altered by Antidepressant Treatment (original) (raw)
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Neuropharmacology, 2008
One of the mechanisms proposed for antidepressant drugs is the enhancement of synaptic connections and plasticity in the hippocampus and cerebral cortex. Fibroblast growth factor 2 (FGF2), is a growth factor essential for the proper formation of synaptic connections in the cerebral cortex, maturation and survival of catecholamine neurons, and neurogenesis. In this report, we attempted to establish a correlation between antidepressant treatments and FGF2 expression in the cerebral cortex and hippocampus, two brain areas relevant for depression. Desipramine (DMI, 10 mg/kg) or fluoxetine (FLU, 5 mg/kg) were injected acutely (single injection) or chronically (daily injection for two weeks) in adult rats. Chronic, but not acute, antidepressant treatments increase FGF2 immunoreactivity in neurons of the cerebral cortex and in both astrocytes and neurons of the hippocampus. FGF2 immunoreactivity in the cortex was increased mainly in the cytoplasm of neurons of layer V. Western blot analyses of nuclear and cytosolic extracts from the cortex revealed that both antidepressants increase FGF2 isoforms in the cytosolic extracts and decrease accumulation of FGF2 immunoreactivity in the nucleus. To characterize the anatomical and cellular specificity of antidepressants, we examined FGF-binding protein (FBP), a secreted protein that acts as an extracellular chaperone for FGF2 and enhances its activity. DMI and FLU increased FBP immunoreactivity in both cortical and hippocampal neurons. Our data suggest that FGF2 and FBP may participate in the plastic responses underlying the clinical efficacy of antidepressants.
Neuropsychopharmacology, 2014
Major depression is a highly prevalent, multidimensional disorder. Although several classes of antidepressants (ADs) are currently available, treatment efficacy is limited, and relapse rates are high; thus, there is a need to find better therapeutic strategies. Neuroplastic changes in brain regions such as the hippocampal dentate gyrus (DG) accompany depression and its amelioration with ADs. In this study, the unpredictable chronic mild stress (uCMS) rat model of depression was used to determine the molecular mediators of chronic stress and the targets of four ADs with different pharmacological profiles (fluoxetine, imipramine, tianeptine, and agomelatine) in the hippocampal DG. All ADs, except agomelatine, reversed the depression-like behavior and neuroplastic changes produced by uCMS. Chronic stress induced significant molecular changes that were generally reversed by fluoxetine, imipramine, and tianeptine. Fluoxetine primarily acted on neurons to reduce the expression of pro-inflammatory response genes and increased a set of genes involved in cell metabolism. Similarities were found between the molecular actions and targets of imipramine and tianeptine that activated pathways related to cellular protection. Agomelatine presented a unique profile, with pronounced effects on genes related to Rho-GTPase-related pathways in oligodendrocytes and neurons. These differential molecular signatures of ADs studied contribute to our understanding of the processes implicated in the onset and treatment of depression-like symptoms.
Neuronal cell adhesion genes and antidepressant response in three independent samples
The pharmacogenomics journal, 2015
Drug-effect phenotypes in human lymphoblastoid cell lines recently allowed to identify CHL1 (cell adhesion molecule with homology to L1CAM), GAP43 (growth-associated protein 43) and ITGB3 (integrin beta 3) as new candidates for involvement in the antidepressant effect. CHL1 and ITGB3 code for adhesion molecules, while GAP43 codes for a neuron-specific cytosolic protein expressed in neuronal growth cones; all the three gene products are involved in synaptic plasticity. Sixteen polymorphisms in these genes were genotyped in two samples (n=369 and 90) with diagnosis of major depressive episode who were treated with antidepressants in a naturalistic setting. Phenotypes were response, remission and treatment-resistant depression. Logistic regression including appropriate covariates was performed. Genes associated with outcomes were investigated in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) genome-wide study (n=1861) as both individual genes and through a pathway ...
P.1.36 Identification and validation of new antidepressant-responsive gene candidates in mouse brain
European Neuropsychopharmacology, 2007
List of abbreviations 119 Assertion 121 List of publications 123 Curriculum vitae 125 1.5 Animal models of depression 1.6 Gene expression studies in mood disorders 1.7 A hypothesis-free approach to identify novel antidepressant-responsive genes in the mouse brain 1.8 Scope of the thesis 1.3 Antidepressant drugs Despite the fact that we still do not understand the aetiology and precise pathophysiology of depression, existing antidepressant treatments are safe and effective, but far from ideal. The therapeutic effects take several weeks to manifest and these effects are often accompanied by unwanted side-effects. Astonishingly enough, fewer than 50% of all patients show full remission after treatment with a single antidepressant drug (for review see: Fava and Kendler, 2000; Nemeroff and Owens, 2002). The history of the treatment of depression started about 50 years ago, when two classes of substances were discovered by serendipity: the monoamine oxidase inhibitors and the tricyclic antidepressants. Most of today's psychopharmacological drugs are based on the mechanism of action of tricyclic antidepressants (TCA), which are believed to act by modulating the serotonin and/or noradrenaline system (Wong and Licinio, 1.4 The hippocampus, depression and neurogenesis One region of high interest in mood disorder research is the hippocampus as receiving input about the "external world" and the homeostatic and emotional "internal world" (Buzsaki, 1996). The hippocampal dentate gyrus receives the principal afferent input about the external world from the entorhinal cortex via the perforant pathway (see figure 2). CA3 neurons in turn receive their main input from the dentate gyrus via the mossy fibres. The CA1 represents the last stage in the intrahippocampal trisynaptic loop and is the major target of CA3 pyramidal cell axons, the Schaffer collaterals. The pathway from CA1 to the subiculum and on to the entorhinal cortex forms the principal hippocampal output (Freund and Buzsaki, 1996). Moreover, the hippocampus receives input from the amygdala and the claustrum, the septal complex and the supramammillary area, the hypothalamus, thalamus and the brainstem. The hippocampus, in turn projects to the septal nuclei, the thalamus, the mamillary and amygdaloid complexes and the striatum (Rosene and Van Hoesen, 1987). The hippocampal formation is part of the limbic system, which is a major centre for emotion formation and processing, for memory, and for learning. Therefore, limbic structures might serve as a link between the stress system and neuropsychiatric disorders (Smith and Vale, 2006). Additionally, the hippocampus plays a role in modulating body physiology, including the activity of the HPA axis, the immune system, blood pressure, and reproductive function. It the causes of human disease. As causes of mood disorders are seldom known, the validity is limited to the hypothesis regarding the possible underlying aetiology (Geyer and Markou, 1995). Some symptoms of major depression are impossible to model in rodents, like thoughts of death or suicide and feelings of worthlessness or guilt, while other symptoms like changes
cDNA gene expression profile of rat hippocampus after chronic treatment with antidepressant drugs
Journal of Neural Transmission, 2003
Background. Chronic antidepressant treatment causes alterations in several hippocampal genes, which participate in neuronal plasticity. However the full picture of their mechanism of action is not known. The advent of genomics enables to identify a broader mechanism of action and identify novel targets for antidepressant development. Methods. The present study examined the cDNA microarray gene expression profile in the hippocampus induced by chronic antidepressant treatment, in rats exposed to the forced swim test. Animals were treated for 2 weeks with moclobemide, clorgyline and amitriptyline. Results. The three antidepressants significantly reduced immobility in the forced swim test and initiated significant homologous changes in gene expressions. These include up regulation of cAMP response element binding protein and down regulation of corticotrophin releasing hormone. Other gene changes noted were those related to neuropeptides, neurogenesis and synaptogenesis, including synaptophysin and neogenin. Some 89 genes were changed by at least 2 drugs, out of which 53 were changed oppositely by forced swim test. Confirmation of gene changes, have come from real time RT-PCR. Conclusions. A significant number and homology in gene expression were observed with the three antidepressants. Many of the genes were associated with neurogenesis and synaptogenesis, including synaptophysin and neogenin.
Molecular Pharmacology, 2002
New experimental evidence suggests that the mechanism of action of antidepressants includes the induction of neurotrophic factor synthesis in selected brain areas. The present study is aimed at establishing whether prolonged antidepressant treatments increase the expression of basic fibroblast growth factor (FGF2), a polypeptide growth factor that has a broad neurotrophic activity in the adult central nervous system. Rats received a single dose or long-term (3 weeks) administration of desipramine (DMI), fluoxetine (FLU), and mianserin (MIA), then were sacrificed at 5 and 24 h after the last injection. RNase protection assay and Western blot analysis revealed that all antidepressant drugs elicited an anatomically specific increase in FGF2 mRNA and protein. The
Antidepressant drug treatment induces Arc gene expression in the rat brain
Neuroscience, 2003
The mechanism underlying the therapeutic effect of antidepressants is not known but neuroadaptive processes akin to long-term potentiation have been postulated. Arc (Activity-regulated, cytoskeletal-associated protein) is an effector immediate early gene implicated in LTP and other forms of neuroplasticity. Recent data show that Arc expression is regulated by brain 5-hydroxytryptamine neurones, a target of many antidepressants. Here in situ hybridisation and immunohistochemistry were used to examine whether Arc expression in rat brain is altered by antidepressant drug treatment. Repeated administration of the monoamine reuptake inhibitors paroxetine, venlafaxine or desipramine induced region-specific increases in Arc mRNA. These increases were greatest in regions of the cortex (frontal and parietal cortex) and hippocampus (CA1 layer) and absent in the caudate putamen. Repeated treatment with the monoamine oxidase inhibitor, tranylcypromine, increased Arc mRNA in a similar fashion to...
Biological Psychiatry, 2008
Background-Brain-derived neurotrophic factor (BDNF) plays an important role in neural plasticity in the adult nervous system and has been suggested as a target gene for antidepressant treatment. The neurotrophic hypothesis of depression suggests that loss of BDNF from the hippocampus contributes to an increased vulnerability for depression, whereas up-regulation of BDNF in the hippocampus is suggested to mediate antidepressant efficacy. Methods-We have used a viral-mediated gene transfer approach to assess the role of BDNF in subregions of the hippocampus in a broad array of behavioral paradigms including depression-like behavior and antidepressant responses. We have combined the adeno-associated virus (AAV) with the Cre/loxP site-specific recombination system to induce the knockout of BDNF selectively in either the CA1 or dentate gyrus (DG) subregions of the hippocampus. Results-We show that the loss of BDNF in either the CA1 or the DG of the hippocampus does not alter locomotor activity, anxiety-like behavior, fear conditioning or depression-related behaviors. However, the selective loss of BDNF in the DG, but not the CA1 region, attenuates the actions of desipramine and citalopram in the forced swim test. Conclusions-These data suggest that the loss of hippocampal BDNF per se is not sufficient to mediate depression-like behavior. However, these results support the view that BDNF in the DG may be essential in mediating the therapeutic effect of antidepressants.