BDNF overexpression in mouse hippocampal astrocytes promotes local neurogenesis and elicits anxiolytic-like activities

• Published in: Translational psychiatry Vol. 3; no. 4; p. e253
• Main Authors: Quesseveur, G, David, D J, Gaillard, M C, Pla, P, Wu, M V, Nguyen, H T, Nicolas, V, Auregan, G, David, I, Dranovsky, A, Hantraye, P, Hen, R, Gardier, A M, Déglon, N, Guiard, B P
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 30.04.2013; Nature Pub. Group
• Subjects: 8-Hydroxy-2-(di-n-propylamino)tetralin; 8-Hydroxy-2-(di-n-propylamino)tetralin - pharmacology; Animals; Antidepressive Agents, Second-Generation; Antidepressive Agents, Second-Generation - pharmacology; Anxiety; Anxiety - drug therapy; Anxiety - metabolism; Anxiety - physiopathology; Astrocytes; Astrocytes - drug effects; Astrocytes - metabolism; Astrocytes - physiology; Behavior, Animal; Behavior, Animal - drug effects; Behavior, Animal - physiology; Brain-Derived Neurotrophic Factor; Brain-Derived Neurotrophic Factor - analysis; Brain-Derived Neurotrophic Factor - metabolism; Brain-Derived Neurotrophic Factor - physiology; Depression; Depression - drug therapy; Depression - metabolism; Depression - physiopathology; Fluoxetine; Fluoxetine - pharmacology; Gene Expression; Gene Expression - physiology; Hippocampus; Hippocampus - chemistry; Hippocampus - drug effects; Hippocampus - metabolism; Hippocampus - physiology; Life Sciences; Male; Mice; Neurogenesis; Neurogenesis - physiology; Original; Piperazines; Piperazines - pharmacology; Pyridines; Pyridines - pharmacology; Serotonin Antagonists; Serotonin Antagonists - pharmacology; Serotonin Receptor Agonists; Serotonin Receptor Agonists - pharmacology
• ISSN: 2158-3188; 2158-3188
• DOI: 10.1038/tp.2013.30

The therapeutic activity of selective serotonin (5-HT) reuptake inhibitors (SSRIs) relies on long-term adaptation at pre- and post-synaptic levels. The sustained administration of SSRIs increases the serotonergic neurotransmission in response to a functional desensitization of the inhibitory 5-HT1A autoreceptor in the dorsal raphe. At nerve terminal such as the hippocampus, the enhancement of 5-HT availability increases brain-derived neurotrophic factor (BDNF) synthesis and signaling, a major event in the stimulation of adult neurogenesis. In physiological conditions, BDNF would be expressed at functionally relevant levels in neurons. However, the recent observation that SSRIs upregulate BDNF mRNA in primary cultures of astrocytes strongly suggest that the therapeutic activity of antidepressant drugs might result from an increase in BDNF synthesis in this cell type. In this study, by overexpressing BDNF in astrocytes, we balanced the ratio between astrocytic and neuronal BDNF raising the possibility that such manipulation could positively reverberate on anxiolytic-/antidepressant-like activities in transfected mice. Our results indicate that BDNF overexpression in hippocampal astrocytes produced anxiolytic-/antidepressant-like activity in the novelty suppressed feeding in relation with the stimulation of hippocampal neurogenesis whereas it did not potentiate the effects of the SSRI fluoxetine on these parameters. Moreover, overexpressing BDNF revealed the anxiolytic-like activity of fluoxetine in the elevated plus maze while attenuating 5-HT neurotransmission in response to a blunted downregulation of the 5-HT1A autoreceptor. These results emphasize an original role of hippocampal astrocytes in the synthesis of BDNF, which can act through neurogenesis-dependent and -independent mechanisms to regulate different facets of anxiolytic-like responses.