ABSTRACT
Both brain-derived neurotrophic factor (BDNF) and the serotonin receptor 2A (5-HT(2A)) have been related to depression pathology. Specific 5-HT(2A) receptor changes seen in BDNF conditional mutant mice suggest that BDNF regulates the 5-HT(2A) receptor level. Here we show a direct effect of BDNF on 5-HT(2A) receptor protein levels in primary hippocampal neuronal and mature hippocampal organotypic cultures exposed to different BDNF concentrations for either 1, 3, 5 or 7 days. In vivo effects of BDNF on hippocampal 5-HT(2A) receptor levels were further corroborated in (BDNF +/-) mice with reduced BDNF levels. In primary neuronal cultures, 7 days exposure to 25 and 50ng/mL BDNF resulted in downregulation of 5-HT(2A), but not of 5-HT(1A), receptor protein levels. The BDNF-associated downregulation of 5-HT(2A) receptor levels was also observed in mature hippocampal organotypic cultures, excluding confounding effects of BDNF on immature tissue. BDNF +/- mice showed significant increased 5-HT(2A) receptor levels in hippocampus confirming the association between 5-HT(2A) receptor and BDNF levels in vivo. In conclusion, our results point to a regulatory role of BDNF on 5-HT2A receptor levels. This interaction may be an important mechanism in the role of BDNF in affective disorders emphasizing the need for further elucidating the specificity and the mechanism behind this regulation.
Subject(s)
Brain-Derived Neurotrophic Factor/genetics , Hippocampus/metabolism , Receptor, Serotonin, 5-HT2A/biosynthesis , Animals , Apoptosis/drug effects , Blotting, Western , Brain-Derived Neurotrophic Factor/biosynthesis , Brain-Derived Neurotrophic Factor/physiology , Cells, Cultured , Down-Regulation/drug effects , Female , Hippocampus/growth & development , Mice , Mice, Knockout , Nerve Tissue Proteins/analysis , Nerve Tissue Proteins/biosynthesis , Organ Culture Techniques , Pregnancy , Rats , Rats, Sprague-Dawley , Synapses/drug effects , Synapses/metabolismABSTRACT
OBJECTIVE: Disturbances in hippocampal neurogenesis may be involved in the pathophysiology of depression and it has been argued that an increase in the generation of new nerve cells in the hippocampus is involved in the mechanism of action of antidepressants. MATERIALS AND METHODS: Adult Wistar rats were treated with fluoxetine (10 mg/kg) 1 h, daily for 5 (subchronic) or 28 days (chronic) before the Novelty Suppressed Feeding test was performed. Cell proliferation and neurogenesis were analysed using the markers 5-bromo-deoxy-2'-uridine, Ki-67, and doublecortin. RESULTS: A significant behavioural effect was found after 28 days of fluoxetine administration. However, no behavioural improvement was demonstrated after acute and subchronic treatment with fluoxetine. We further demonstrate that chronic antidepressant treatment increases cell proliferation as well as neurogenesis in the dentate gyrus, here using Wistar rats. CONCLUSIONS: In further development of antidepressants, neurogenesis may serve as an important parameter to examine the efficacy and mechanism of action of novel drugs.
Subject(s)
Behavior, Animal/drug effects , Cell Proliferation/drug effects , Fluoxetine/administration & dosage , Neurons/drug effects , Selective Serotonin Reuptake Inhibitors/administration & dosage , Animals , Bromodeoxyuridine/metabolism , Cell Count , Dentate Gyrus/cytology , Doublecortin Domain Proteins , Doublecortin Protein , Drug Administration Schedule , Feeding Behavior/drug effects , Ki-67 Antigen/metabolism , Male , Microtubule-Associated Proteins/metabolism , Neuropeptides/metabolism , Rats , Rats, Wistar , Reaction Time/drug effectsABSTRACT
Aggregation of the beta-amyloid protein (Abeta) is a hallmark of Alzheimer's disease (AD) and is believed to be causally involved in a neurodegenerative cascade. In patients with AD, reduced levels of serum Brain Derived Neurotrophic Factor (BDNF) and cortical 5-HT(2A) receptor binding has recently been reported but it is unknown how these changes are related to beta-amyloid accumulation. In this study we examined in rats the effect of intrahippocampal injections of aggregated Abeta(1-42) (1 microg/microl) on serum and brain BDNF or 5-HT(2A) receptor levels. A social recognition test paradigm was used to monitor Abeta(1-42) induced memory impairment. Memory impairment was seen 22 days after injection of Abeta(1-42) in the experimental group and until termination of the experiments. In the Abeta(1-42) injected animals we saw an abolished increase in serum BDNF levels that was accompanied by significant lower BDNF levels in frontal cortex and by an 8.5% reduction in hippocampal 5-HT(2A) receptor levels. A tendency towards lowered cortical 5-HT(2A) was also observed. These results indicate that the Abeta(1-42) associated memory deficit is associated with an impaired BDNF regulation, which is reflected in lower cortical BDNF levels, and changes in hippocampal 5-HT(2A) receptor levels. This suggests that the BDNF and 5-HT2A changes observed in AD are related to the presence of Abeta(1-42) deposits.
