Antidepressants act on glia cells: Calcium responses of astrocytes to citalopram and fluoxetine in the mouse brain

Synaptic transmission is directly influenced by astrocytes, the most numerous cell type in the mammalian brain. An active role for astrocytes in memory processing is more and more recognized, but the role of astrocytes in mood disorders and the modes of action of antidepressant drugs have yet to be elucidated. In order to investigate the role of astrocytes in MDD and the mode of action of SSRIs, we loaded astrocytes in acute slices of the mouse prefrontal cortex with the calcium-sensitive dye Fluo-4 and analyzed the astrocyte calcium responses to stimulation with citalopram, fluoxetine or 5-HT directly. We found that citalopram and fluoxetine induce calcium signals in a subset of astrocytes also when neuronal signal propagation is inhibited. The calcium transients in individual astrocytes occur delayed and not all at once, in contrast to the response to ATP or glutamate. These responses were also observed after the application of 5-HT. Responses to 5-HT could mostly not be evoked twice. Using pharmacological approaches, we determined glutamate as a substance that leads to the modulation of the 5-HT-induced calcium signal in astrocytes. Thus, responses to stimulation of glutamatergic and serotonergic receptors on astrocytes are functionally interfering. We speculate that this neuron-glia interaction which may play a role in the disturbed balance of neurotransmitter systems in MDD is modified by citalopram and fluoxetine.