Glia and immune cell signaling in bipolar disorder: insights from neuropharmacology and molecular imaging to clinical application

Abstract

Bipolar disorder (BD) is a debilitating mental illness characterized by severe fluctuations in mood, sleep, energy and executive functioning. Pharmacological studies of selective serotonin reuptake inhibitors and the monoamine system have helped us to clinically understand bipolar depression. Mood stabilizers such as lithium and valproic acid, the first-line treatments for bipolar mania and depression, inhibit glycogen synthase kinase-3 beta (GSK-3β) and regulate the Wnt pathway. Recent investigations suggest that microglia, the resident immune cells of the brain, provide a physiological link between the serotonin system and the GSK-3β/Wnt pathway through neuroinflammation. We review the pharmacological, translational and brain imaging studies that support a role for microglia in regulating neurotransmitter synthesis and immune cell activation. These investigations provide a model for microglia involvement in the pathophysiology and phenotype of BD that may translate into improved therapies.

The ups and downs of cellular stress: the “MAM hypothesis” for Bipolar disorder pathophysiology

“…Furthermore, activation of the immune system has been consistently reported in BD [120,121] and in the last few years, evidence has been emerged implying activation of the NLRP3 inflammasome in BD pathophysiology [17]. Altered levels of inflammatory cytokines were shown in the brain and periphery of patients with BD, suggesting that activation of the inflammatory system may play a role in the pathophysiology of BD [120].…”

Kinins and microglial responses in bipolar disorder: a neuroinflammation hypothesis

“…It has been proposed that activated microglial cells release interferon (IFN)-γ enhancing the activation of the kynurenine pathway (Watkins et al, 2014). This activation would eventually result in an increase of indoleamine 2,3-dioxygenase (IDO) activity, which is responsible for tryptophan and serotonin degradation.…”

“…It is still unknown why the number of glial cells is reduced even when gliosis is present in BD. It has been previously suggested that microglial cells might show reduced proliferation rates before BD onset, while cell degeneration might occur as a result of extensive inflammation due to microglia activation triggered by gliosis (Watkins et al, 2014). Additionally, histological brain analysis of frontal cortex samples showed an up-regulation of the pro-inflammatory and excitotoxicity-related proteins IL-1β, IL-1 receptor, iNOS and c-Fos suggesting that increased expression and activity rates of these might lead to cell death, brain atrophy and cognitive decline, as previously described for BD pathology (Rao et al, 2010).…”

“…At the molecular level, BD is characterized by a reduction in serotonin and BDNF levels, dysfunctions in neuronal plasticity, gliosis and mainly neuroinflammation (Schneider et al, 2012;Stertz et al, 2013;Watkins et al, 2014). The reduction in serotonin and BDNF levels are due to the expression of pro-inflammatory cytokines (Koo and Duman, 2008;Miller et al, 2009;Catena-Dell'Osso et al, 2013).…”

“…The main consequence is the depletion of tryptophan, a serotonin precursor, compromising serotonin protein levels (Berk et al, 2011), while, at the same time, altering BDNF protein expression. Watkins and colleagues proposed that mania and depression stages seen in BD are due to a deregulated kynurenine pathway (Watkins et al, 2014).…”