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.
Highlights
Depression is the neuropsychiatric disorder with higher incidence worldwide, representing a major socio-economical burden (Kessler et al, 2003)
Recent studies in adrenalectomized animals revealed an impact of ghrelin rather than glucocorticoids in formatting the emotional disturbances associated with repeated stress (Meyer et al, 2014). Another lead for the neurobiology of depression is based on the clinical use of serotonin-selective reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) to manage depression, which hints at the dysfunction of the neuromodulation by serotonin and other biogenic amines in depression (Krishnan and Nestler, 2008)
A major breakthrough in understanding depression was the observation that sub-anesthetic doses of ketamine, an NMDA receptor antagonist, can revert rapidly symptoms of depression, with a long-lasting antidepressant effect (2 weeks; Berman et al, 2000; Zarate et al, 2006)
Summary
Depression is the neuropsychiatric disorder with higher incidence worldwide, representing a major socio-economical burden (Kessler et al, 2003). Depressive conditions display heterogeneous presentations and are defined clinically based on different affective symptoms (sadness, desperation, apathy, anhedonia, sensation of discomfort) that decrease interest in daily. Understanding the causes and neurobiological basis of depression remains a challenge, probably due to the lack of faithful animal models (Berton et al, 2012). The relation between cumulative stress and the incidence of depression (de Kloet et al, 2005) and the prevalence of depression in suicide completers (Coryell and Young, 2005), provide two windows of opportunities to indirectly study the neurobiological basis of depression using chronically stressed animals and brain samples from suicide completers
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