title: Depression as a Glial-Based Synaptic Dysfunction.
abstract: Recent studies combining pharmacological, behavioral, electrophysiological and molecular approaches indicate that depression results from maladaptive neuroplastic processes occurring in defined frontolimbic circuits responsible for emotional processing such as the prefrontal cortex, hippocampus, amygdala and ventral striatum. However, the exact mechanisms controlling synaptic plasticity that are disrupted to trigger depressive conditions have not been elucidated. Since glial cells (astrocytes and microglia) tightly and dynamically interact with synapses, engaging a bi-directional communication critical for the processing of synaptic information, we now revisit the role of glial cells in the etiology of depression focusing on a dysfunction of the "quad-partite" synapse. This interest is supported by the observations that depressive-like conditions are associated with a decreased density and hypofunction of astrocytes and with an increased microglia "activation" in frontolimbic regions, which is expected to contribute for the synaptic dysfunction present in depression. Furthermore, the traditional culprits of depression (glucocorticoids, biogenic amines, brain-derived neurotrophic factor, BDNF) affect glia functioning, whereas antidepressant treatments (serotonin-selective reuptake inhibitors, SSRIs, electroshocks, deep brain stimulation) recover glia functioning. In this context of a quad-partite synapse, systems modulating glia-synapse bidirectional communication-such as the purinergic neuromodulation system operated by adenosine 5'-triphosphate (ATP) and adenosine-emerge as promising candidates to "re-normalize" synaptic function by combining direct synaptic effects with an ability to also control astrocyte and microglia function. This proposed triple action of purines to control aberrant synaptic function illustrates the rationale to consider the interference with glia dysfunction as a mechanism of action driving the design of future pharmacological tools to manage depression.
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of CoimbraCoimbra, Portugal; Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, SCBrazil.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rial
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra Coimbra, Portugal.
authors.forename: Cristina
authors.initials: C
authors.lastname: Lemos
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra Coimbra, Portugal.
authors.forename: Helena
authors.initials: H
authors.lastname: Pinheiro
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra Coimbra, Portugal.
authors.forename: Joana M
authors.initials: JM
authors.lastname: Duarte
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra Coimbra, Portugal.
authors.forename: Francisco Q
authors.initials: FQ
authors.lastname: Gonçalves
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra Coimbra, Portugal.
authors.forename: Joana I
authors.initials: JI
authors.lastname: Real
authors.affiliation: Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, SC Brazil.
authors.forename: Rui D
authors.initials: RD
authors.lastname: Prediger
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra Coimbra, Portugal.
authors.forename: Nélio
authors.initials: N
authors.lastname: Gonçalves
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of CoimbraCoimbra, Portugal; Faculty of Medicine, University of CoimbraCoimbra, Portugal.
authors.forename: Catarina A
authors.initials: CA
authors.lastname: Gomes
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra Coimbra, Portugal.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Canas
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of CoimbraCoimbra, Portugal; Faculty of Medicine, University of CoimbraCoimbra, Portugal.
authors.forename: Paula
authors.initials: P
authors.lastname: Agostinho
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of CoimbraCoimbra, Portugal; Faculty of Medicine, University of CoimbraCoimbra, Portugal.
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Cunha
keywords: astrocytes; depression; microglia; purines; synapse
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