Title:The Monoaminergic Tripartite Synapse: A Putative Target for Currently Available Antidepressant Drugs
Volume: 14
Issue: 11
Author(s): Gaël Quesseveur, Alain M. Gardier and Bruno P. Guiard
Affiliation:
Keywords:
Antidepressants, astrocytes, depression, gliotransmitters, neurotrophic factors, tripartite synapse.
Abstract: Antidepressant drugs such as the serotonin (5-HT)/norepinephrine (NE) and dopamine (DA) reuptake inhibitors
activate monoaminergic neurotransmission in various brain regions, such as the amygdala, the frontal cortex or the hippocampus.
Although this property is well established, the post-synaptic mechanisms by which these pharmacological agents
exert therapeutic activity in major depressive disorders (MDD) is not fully understood. Recent clinical and preclinical
studies have indicated that the density and reactivity of glia and more particularly of astrocytes are reduced in MDD patients.
These data along with the fact that astrocytes express monoaminergic transporters and receptors make these cells
putative targets for antidepressant treatments. Accordingly, in vitro evidence has demonstrated that the application of
various classes of antidepressant drugs on rodent primary astrocyte cultures elicits a wide spectrum of responses, from the
rise in cytosolic calcium concentrations, as a marker of cellular activity, to the release of glucose metabolites, gliotransmitters
and neurotrophic factors. Remarkably, antidepressant drugs also attenuate the release of inflammatory molecules
from reactive astrocytes or microglia, suggesting that part of the beneficial effects in depressed patients or animal models
of depression might result from the ability of antidepressants to regulate the synthesis and release of psychoactive substances
acting on both pre- and post-synaptic neurons. Among the many long-term targets of antidepressant drugs, brainderived
neurotrophic factor (BDNF) has been well studied because of the positive influence on adult hippocampal neurogenesis,
synaptogenesis and the local serotonergic tone. This review will illustrate how the concept of the tripartite synapse,
which is classically associated with different forms of plasticity involving glutamate, could be expanded to the
monoaminergic systems to regulate antidepressant drug responses. The recent in vivo data supporting that hippocampal astrocytes
act in concert with neurons to release BDNF under pharmacological conditions and thereby regulate different facets
of anxiolytic-/antidepressant-like activities through neurogenesis-dependent and independent mechanisms will be emphasized.
