Anti-Depressant Fluoxetine Reveals its Therapeutic Effect Via Astrocytes

Abstract

Although psychotropic drugs act on neurons and glial cells, how glia respond, and whether glial responses are involved in therapeutic effects are poorly understood. Here, we show that fluoxetine (FLX), an anti-depressant, mediates its anti-depressive effect by increasing the gliotransmission of ATP. FLX increased ATP exocytosis via vesicular nucleotide transporter (VNUT). FLX-induced anti-depressive behavior was decreased in astrocyte-selective VNUT-knockout mice or when VNUT was deleted in mice, but it was increased when astrocyte-selective VNUT was overexpressed in mice. This suggests that VNUT-dependent astrocytic ATP exocytosis has a critical role in the therapeutic effect of FLX. Released ATP and its metabolite adenosine act on P2Y ₁₁ and adenosine A2b receptors expressed by astrocytes, causing an increase in brain-derived neurotrophic factor in astrocytes. These findings suggest that in addition to neurons, FLX acts on astrocytes and mediates its therapeutic effects by increasing ATP gliotransmission.

Highlights

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  Anti-depressant FLX acts on astrocytes and increases VNUT-dependent ATP exocytosis.

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  Such astrocytic responses are responsible for the FLX-induced therapeutic effects.

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  Astrocytic ATP and its metabolite adenosine increase BDNF in astrocytes, and reveal the therapeutic effects.

Kinoshita et al. demonstrated that astrocytes are a therapeutic target of the antidepressant, fluoxetine (FLX). They found that FLX stimulates VNUT-dependent ATP release from astrocytes leading to a BDNF-mediated anti-depressive effect. This study demonstrated the astrocytic regulation of this anti-depressive effect, which complements the previously described conventional mechanism of FLX. Because the involvement of astrocytes in the pathogenesis of depression is of current interest, this new insight into the role of astrocytes in anti-depressive effects should support the establishment of novel therapeutic strategies for depression.