Depression as a Glial-Based Synaptic Dysfunction.
Front. Cell. Neurosci.. 2016-01-22; 9:
DOI: 10.3389/fncel.2015.00521
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Rial D(1), Lemos C(2), Pinheiro H(2), Duarte JM(2), Gonçalves FQ(2), Real JI(2), Prediger RD(3), Gonçalves N(2), Gomes CA(4), Canas PM(2), Agostinho P(4), Cunha RA(4).
Author information:
(1)CNC – Center for Neuroscience and Cell Biology, University of CoimbraCoimbra, Portugal; Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, SCBrazil.
(2)CNC – Center for Neuroscience and Cell Biology, University of Coimbra Coimbra, Portugal.
(3)Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, SC Brazil.
(4)CNC – Center for Neuroscience and Cell Biology, University of CoimbraCoimbra, Portugal; Faculty of Medicine, University of CoimbraCoimbra, Portugal.
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.