Abstract
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.
Highlights
The therapeutic activity of selective serotonin (5-HT) reuptake inhibitors (SSRIs) relies on long-term adaptation at pre- and post-synaptic levels
We examined whether the brainderived neurotrophic factor (BDNF)-engineered lentiviral vector increased the levels of activated extracellular signal-regulated kinase (ERK) and Akt in the rat hippocampus as an indirect marker of BDNF secretion
To further investigate the cellular mechanisms underlying the behavioral effects of BDNF, we evaluated the impact of BDNF overexpression in hippocampal astrocytes on adult hippocampal neurogenesis, which has been proposed as relevant for antidepressant action.[1,5]
Summary
The therapeutic activity of selective serotonin (5-HT) reuptake inhibitors (SSRIs) relies on long-term adaptation at pre- and post-synaptic levels. At the post-synaptic level, compelling evidence has demonstrated that the sustained, but not acute, administration of SSRIs stimulates adult hippocampal neurogenesis, whereas the disruption of this phenomenon prevents the behavioral effects of these antidepressants in mice.[1] the complex biological and psychobiological changes associated with depression and related treatments cannot be attributed to neurogenesis alone,[2] this particular property of SSRIs has been reported in humans[3] and in nonhuman primates.[4] We recently demonstrated that the disruption of adult hippocampal neurogenesis compromises the anxiolytic-/antidepressant-like activity of the SSRI fluoxetine in some, but not all, behavioral paradigms, thereby suggesting the existence of both neurogenesis-dependent and neurogenesis-independent mechanisms of action.[5] A number of factors have been proposed to participate in SSRI-induced adult hippocampal neurogenesis. Among the many long-term targets of SSRI treatments, neurotrophins, brainderived neurotrophic factor (BDNF), have been well studied
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