Page 136 - Read Online

individuals compared to 13 healthy controls. Steiner in which increased inflammatory cytokines were
et al. [19] observed increased microglial cell numbers in observed. [24] They cannot affect brain functions until
the anterior cingulate cortex and mediodorsal thalamus inflammatory mediators do alter the integrity of
of two individuals who committed suicide during blood-brain barrier. However, when a blood-brain
acute psychosis. However, no effect of diagnosis on barrier alteration occurs, antibodies may presumably
the microglial density but only significant microgliosis cross-react with the subunits of NMDAR on glial
was reported in dorsolateral prefrontal cortex, cells inducing the abnormal release of glutamate.
anterior cingulate cortex, mediodorsal thalamus, and This enhanced activation of glial cells is associated
hippocampus of 16 schizophrenic and 14 depressed with glutamatergic excitotoxicity, apoptosis, and
subjects died by suicide. [20] The authors hypothesized clinically significant behavioral changes. [25,26] Also, as
that the link between microglial activation and suicidal suggested by Santello et al., [27] tumor necrosis factor
behavior may be mediated by neuroendocrine factors alpha (TNF-a) controls the neuromodulatory action of
such as inflammatory cytokines and oxidative stress. dentate granule cell synapses in astrocytes, through
Finally, Dean et al. [21] showed that CD11b (a potential Ca -dependent glutamate release and pre-NMDAR
2+
microglia/macrophages marker) was not increased activation. Therefore, gliotransmission together with
in the cortex of ten subjects with MDD, and ten with its synaptic effects seem to be controlled not only by
2+
bipolar disorder. astrocyte Ca elevations but also by homeostatic factors
such as TNF-a. Previous studies have shown that both
To the best of our knowledge, there are no reports the excitatory neurotransmitter glutamate and the
in the current literature concerning the association proinflammatory cytokine TNF-a may be considered
between microglial glutamatergic abnormalities as effectors of microglial-stimulated death. [28]
and MDD/suicidal behavior with the exception
of the review of Niciu et al. [22] suggesting that Recently, Schnieder et al. [29] also found a 18% greater
glial-mediated glutamatergic dysfunction is a common density of perivascular cells in dorsal white matter
neuropathological pathway in patients with substance prefrontal cortex of 11 subjects died by suicide
use disorders and MDD. suggesting the induction of important alterations in the
characteristics of blood-brain barrier in microglia cells of
It is currently unclear whether microglial abnormal these individuals. Autoimmune activity directed against
activation may directly induce psychopathological serotonin may directly compromise serotonergic axons
conditions, should be considered an epiphenomenon and their functioning with the final result of relevant
of other related processes associated, in turn, with deficits in serotonergic neurotrasmission. Serotonin
psychopathological conditions, or alternatively may be disrupted by abnormal (e.g. hyperactivated)
a nonspecific tissue reaction independent of pathways such as that of kynurenine inside microglial
psychopathology. Another controversial issue cells due to the enhanced metabolism of tryptophan to
concerns the exact relationship between inflammatory quinolinic acid. [30,31]
stressful stimuli, autoimmunity, and abnormalities in
glutamatergic activity. Elevated levels of kynurenic acid, an astrocyte-derived
metabolite of the kynurenine pathway has been reported
The sequence of molecular events underlying MDD to significantly reduce glutamate release in some brain
and suicidal behavior is still poorly understood. regions such as the hippocampus. [32,33] Also, increased
Microglia and monocytes are usually involved in the micromolar levels of kynurenic acid have been suggested
integration of sensory information within the peripheral to inhibit a-amino-3-hydroxy-5-methyl-4-isoxazole
sensory nerves and endocrine system. [23] Stress and proprionic acid and kainate receptors. [34,35]
other signaling molecules (e.g. cytokines, oxidative
free radicals) may activate the oxidation sensitive Inflammatory cytokines may further induce the
transcription factor nuclear factor-κB (NF-κB), which abnormal release of quinolinic acid in microglia [36]
is highly expressed in microglia with the final result related to aberrant stimulation of neurons in the ventral
of increased NF-κB-DNA binding and transcription prefrontal cortex and altered connectivity between
of genes encoding for chemokines, cytokines, and cortical structures and limbic system.
oxidases/proteases. As suggested by the same authors,
[24]
microglia reported morphological changes in response The critical role of quinolinic acid in microglia-abnormal
to exposure to both environmental and internal stimuli. activation has been also demonstrated by the elevated
levels of indoleamine 2,3-dioxygenase and kynurenine
Furthermore, antibodies against serotonin have been monooxygenase in the quinolinic acid biosynthesis
commonly found in more than 50% of depressed pathway in CX3CR1 knockout mice. [37] Notably,
patients and importantly, in all those conditions recent compounds with antidepressant properties

128 Neuroimmunol Neuroinflammation | Volume 2 | Issue 3 | July 15, 2015 Neuroimmunol Neuroinflammation | Volume 2 | Issue 3 | July 15, 2015 129