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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_205_библиотеки_им_акад_М_И_Перельмана
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PART III
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Investigating Mood Disorders
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CHAPTER 9
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Anatomical Pathology
Grazyna Rajkowska, Ph.D.
In people with mood disorders such as major depressive disorder
(MDD) and bipolar disorder, brain imaging studies show reductions in volume,
blood flow, and metabolism and altered connectivity in frontolimbic brain regions
Chapter 11, “Brain Imaging,” in this text). Changes in the number and density of
(see
neurons and glial cells in people with mood disorders represent a potential cellular
and molecular basis for the aberrant in vivo morphology and functions of the fronto
limbic brain regions.
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Glial Pathology
Prominent decreases in the number and density of glial cells have been the most consistent cellular abnormality identified in mood disorders. As discussed in this section,
early studies reported postmortem pathology of a nonspecific Nissl-stained popula
tion of glial cells in MDD and bipolar disorder, and subsequent studies using immunohistochemistry found morphometric alterations in specific types of glial cells such as
astrocytes, oligodendrocytes, and microglia.
General Population of Glial Cells
Decreases in the number and density of a general or nonspecific population of Nisslstained glial cells were reported by independent laboratories in frontolimbic brain regions in MDD and bipolar disorder. A significant decrease in the number of glial cells
was found in the subgenual anterior cingulate cortex in a small subgroup of subjects
with either familial MDD or familial bipolar disorder, in comparison with controls
(Ongür et al. 1998). Cell number in this study was estimated across all six cortical layers, with no information on laminar specificity of glial loss. In finer detail, reductions
in glial cell density were observed in layer VI of the supragenual anterior cingulate
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cortex (Cotter et al. 2001), in layers III and V of the dorsolateral prefrontal cortex (Cotter et al. 2002b; Rajkowska et al. 1999, 2001), and in layers III–VI of the caudal orbitofrontal cortex (Rajkowska et al. 1999) in subjects with mood disorders. Another study
found decreases in glial cell density in layers II–VI of the anterior cingulate cortex
(Gittins and Harrison 2011). However, glial cell pathology in mood disorders is not
noted throughout the cerebral cortex. Ongür et al. (1998) found no changes in the
number of glial cells in the sensorimotor cortex in either MDD or bipolar disorder,
whereas other researchers reported no changes in glial density in the supragenual
part of the anterior cingulate cortex or the entorhinal cortex in bipolar disorder or
MDD, or in the rostral orbitofrontal cortex in MDD (Bowley et al. 2002; Chana et al.
2003; Rajkowska et al. 1999).
Glial pathology in mood disorders has also been studied in subcortical structures.
Two studies found a significant decrease in glial cell density in the amygdala in sub
jects with MDD and unmedicated subjects with bipolar disorder (Bowley et al. 2002;
Hamidi et al. 2004). However, other studies of the amygdala found no changes in the
total number or density of glial cells in subjects with MDD or bipolar disorder (Bezchlibnyk et al. 2007; Rubinow et al. 2016). Likewise, in the hippocampus there was no
significant difference between MDD and control subjects in total number or density
of glial cells (Cobb et al. 2013).
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Astrocytes
Astrocytes are the most numerous and versatile type of glial cells in the CNS. They
are crucial to the neuronal microenvironment because of their role in regulating glu
cose metabolism, glutamate uptake, synaptic development and maturation, and the
blood-brain barrier. Astrocytes have been suggested to be major contributors to gen
eral pathology of glial cells in mood disorders, as observed in postmortem studies
(Rajkowska and Stockmeier 2013).
Decreases in astrocyte cell density and disruption in the cells’ integrity have been
reported in frontolimbic brain regions in MDD or bipolar disorder. Immunohisto
chemical examination of astrocytes using an antibody to glial fibrillary acidic protein
(GFAP) in the gray matter of the dorsolateral prefrontal cortex revealed significant de
creases in the density of astrocytes in a subgroup of younger patients (ages 30–45
years) with MDD as compared with younger control subjects and older patients (ages
46–86 years) with MDD (Miguel-Hidalgo et al. 2000). GFAP is a marker of astrocytes
and an indicator of their integrity. Subsequently, GFAP levels were reduced in the
same cortical region in these younger subjects with MDD as compared to age-matched
control subjects, and GFAP levels were positively correlated with both age at onset of
depression and age at time of death (Si et al. 2004). Together, these studies suggest that
astrocyte pathology is characteristic of early-onset depression. Another study noted
that later-onset depression features neuronal pathology (Rajkowska et al. 2005).
In addition to studies that examined astrocytes in cortical gray matter, other studies
reported alterations in astrocyte pathology in frontal white matter in mood disorders.
Reduced GFAP, detected autoradiographically, was observed in the white matter of the
anterior cingulate cortex in a cohort including subjects with mood disorder (MDD or
bipolar disorder) (Gittins and Harrison 2011). Enlarged cell bodies of white matter astrocytes were detected in the anterior cingulate cortex in depressed subjects who died
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by suicide (Torres-Platas et al. 2011). In another study, in the white matter of orbitofrontal cortex, no changes in the size of astrocyte cell bodies were noted; however, the
density of GFAP-positive astrocytes and area fraction was decreased in MDD (Raj
kowska et al. 2018). Decreased area fraction, but not density of GFAP immunostaining,
was reported in the white matter adjacent to the dorsolateral prefrontal cortex in sub
jects with bipolar disorder (Hercher et al. 2014). Astrocyte pathology in cortical white
matter may affect the changes in axon integrity that have been seen in neuroimaging
studies in mood disorders, and thereby interfere with signal conduction.
Subcortical structures also exhibit astrocyte pathology. A decrease in the density of
astrocytes positive for S100 calcium-binding protein B (S100B), a marker that is abun
dant in astrocytes, was identified in the hippocampus in subjects with MDD or bipolar disorder (Gos et al. 2013). The density of astrocytes labeled with GFAP, a marker of
astrocyte integrity, was decreased in the hippocampus in MDD (Müller et al. 2001), but
this decrease was only in MDD in the absence of an antidepressant drug (Cobb et al.
2016). This latter observation is supported by the study of an animal model of depres
sion, suggesting that antidepressants can prevent an astrocyte deficit in the hippocampus in MDD (Czéh and Nagy 2018). The density of GFAP-positive astrocytes was
also decreased in the amygdala in MDD but not in bipolar disorder (Altshuler et al.
2010). In addition, reduced GFAP expression was observed in the locus coeruleus
(Chandley et al. 2013) and in the cerebellum (Fatemi et al. 2004) in MDD. Finally, the
expression of GFAP mRNA and protein was decreased in the thalamus and caudate
nucleus of depressed subjects who died by suicide, indicating dysfunction in astro
cytes and their genes in these brain structures (Torres-Platas et al. 2016).
Furthermore, pathology in astrocytes in MDD is evident in studies on astrocytic
endfeet, astrocytic gap junction channels, and astrocytic glutamate transporters. Each
of these measures provides an assessment of the quantity and health of astrocytes.
The coverage of blood vessels by astrocytic endfeet expressing aquaporin-4 was reduced in the orbitofrontal cortex in MDD, suggesting impaired blood flow and glucose uptake by astrocytes (Rajkowska et al. 2013). Decreased density and size of gap
junctions and levels of connexin 43, the main protein subunit of astrocyte gap junc
tions, were detected in the orbitofrontal cortex in MDD (Miguel-Hidalgo et al. 2014).
Furthermore, there was a downregulation of connexin 43 and connexin 30 mRNA in
several brain regions of depressed subjects who died by suicide (Nagy et al. 2017);
downregulation of these mRNAs suggests that decreases in astrocyte connexins are
related to a decrease in the gene expression of these connexins. Changes in connexins
in MDD likely alter the diffusion of ions and small molecules between astrocytes via
gap junctions and may alter neurotransmission. Other proteins expressed by astro
cytes, such as glutamate transporters and glutamine synthetase, were also decreased
in the prefrontal cortex in MDD (Choudary et al. 2005; Miguel-Hidalgo et al. 2010),
supporting the hypothesis of glutamatergic dysfunction in depression noted in clinical studies and animal models (Arnone et al. 2015).
Astrocyte dysfunction was reported in a molecular study investigating genomewide differential methylation associated with depression and suicide (Nagy et al.
2015). Significant differences in the methylation patterns specific to astrocytic dysfunction were observed in the dorsolateral prefrontal cortex in subjects with MDD
who died by suicide. Thus, astrocyte dysfunction in depression could involve epigenetic factors, such as DNA methylation, that modulate gene expression.
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Oligodendrocytes
Oligodendrocytes support and insulate axons by creating the myelin sheath. Consequently, oligodendrocyte pathology can cause abnormal development, demyelination,
or reduction of myelinated axons, which can alter neuronal circuitry in mood disor
ders. The involvement of oligodendrocytes in glial pathology is suggested in MDD
and bipolar disorder.
Reductions in the level of myelin basic protein, a marker for mature oligodendrocytes, were found in the anterior frontal cortex of depressed subjects who died by suicide (Honer et al. 1999). In other studies, ultrastructural changes in oligodendrocytes
suggestive of apoptosis and necrosis were observed in the anterior frontal cortex in
bipolar disorder (Uranova et al. 2001), and there were significant decreases in the cell
density of Nissl-stained oligodendrocytes in layer VI of the dorsolateral prefrontal
cortex in MDD and bipolar disorder (Uranova et al. 2004). In addition, there was a
prominent reduction in the number of perineuronal oligodendrocytes in layer III in
the dorsolateral prefrontal cortex in MDD and bipolar disorder (Vostrikov et al. 2007).
Reduced density of oligodendrocytes was also found in the anterior frontal cortex in
MDD (Hayashi et al. 2011).
Oligodendrocyte morphometry in frontal white matter has also been examined in
mood disorders. Increased density of Nissl-stained oligodendrocytes was reported in
the white matter of the dorsolateral prefrontal cortex in bipolar disorder (Hercher et
al. 2014). Reductions in soma size of CNPase-positive oligodendrocytes, but not cell
density, were observed in the white matter underlying the ventral prefrontal cortex in
MDD (Rajkowska et al. 2015). Finally, greater thickness of myelinated fibers was detected in the genu of the corpus callosum in MDD (Williams et al. 2015).
Oligodendrocyte pathology was also reported in subcortical structures in mood
disorders. In a study in the amygdala, in which oligodendrocytes were identified
solely by morphometry in Nissl-stained sections, the density of oligodendrocytes was
decreased in subjects with MDD and in unmedicated subjects with bipolar disorder
(Bowley et al. 2002). In bipolar disorder, the density of oligodendrocytes immuno
stained with S100B, a marker of oligodendrocyte integrity, was decreased in the hippocampus (Gos et al. 2013).
Molecular pathology of oligodendrocytes has been reported in mood disorders.
The expression of key oligodendrocyte-specific and myelin-associated genes is decreased in the dorsolateral prefrontal cortex in bipolar disorder (Tkachev et al. 2003)
and in the temporal cortex in MDD (Aston et al. 2005). Another study found increased
or decreased expression of similar genes (per Aston et al.) in the white matter of the
ventral prefrontal cortex in MDD (Rajkowska et al. 2015). Cellular and molecular pathology of oligodendrocytes may underlie the altered frontolimbic connectivity seen
with diffusion tensor imaging in MDD and bipolar disorder (reviewed in Czéh and
Nagy 2018).
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Microglia
Microglia, the third type of glial cells, are the primary immune cells of the CNS and
are functionally similar to peripheral macrophages. Microglia act as the major inflammatory cell type in the brain, so abnormalities in microglia support the hypothesis
that neuroinflammation contributes to the pathophysiology of depression (Mecha-
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war and Savitz 2016; Rosenblat et al. 2014; Yirmiya et al. 2015). For example, activated
microglia are reported in the hippocampus, anterior cingulate cortex, prefrontal cortex,
and thalamus of the postmortem brains of depressed subjects and depressed subjects
who died by suicide (Bayer et al. 1999; Steiner et al. 2008; Torres-Platas et al. 2014). A
recent review of postmortem studies notes changes in microglial neuroinflammatory
markers in the frontal cortex, dorsal raphe, and hippocampus in bipolar disorder (Gi
ridharan et al. 2020). Altered neuroinflammatory gene expression has been detected
in the prefrontal cortex and hippocampus in MDD (Mahajan et al. 2018; Shelton et al.
2011). Moreover, there is increased density of the translocator protein, a marker of ac
tivated microglia and neuroinflammation, in the prefrontal cortex, anterior cingulate
cortex, hippocampus, and insula during major depressive episodes (Setiawan et al.
2015). Another in vivo study provides evidence for focal neuroinflammation in the
hippocampus but not prefrontal cortex in bipolar disorder (Haarman et al. 2014).
Neuronal Pathology
Neuronal pathology in mood disorders is less obvious than glial pathology because
the former is found in fewer brain regions than glial pathology (Bowley et al. 2002;
Cotter et al. 2001, 2002b; Ongür et al. 1998). Moreover, if changes in neuronal density
and/or size are detected, these changes are smaller in magnitude than those in glial
cells. Neuronal pathology is not evident when the general population of Nissl-stained
neurons is analyzed (Cotter et al. 2002b; Ongür et al. 1998; Rajkowska et al. 1999,
2001). Significant reductions are found in both MDD and bipolar disorder only when
neurons are analyzed in individual cortical layers or in size-dependent or immunohistochemistry-dependent separate subtypes.
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Cerebral Cortex
In postmortem studies of mood disorders, reductions in neuronal density and soma
size have been found in association cortices but not in the primary sensory cortical re
gions. The density of large neurons was decreased in layers II–VI of the dorsolateral
prefrontal and orbitofrontal cortices in MDD (Rajkowska et al. 1999). In addition, in
MDD, smaller sizes of neuronal cell bodies were reported in certain layers in these
same brain regions plus the anterior cingulate cortex (Cotter et al. 2001, 2002b; Rajkowska et al. 1999). Decreases in laminar neuronal density were also detected in the
dorsolateral prefrontal and anterior cingulate cortices in bipolar disorder (Benes et al.
2001; Bouras et al. 2001; Cotter et al. 2002a; Rajkowska et al. 2001). Moreover, reduced
density of layer II nonpyramidal (presumably GABAergic) neurons and of layer III
and V pyramidal (presumably glutamatergic) neurons was observed in the same
brain regions in bipolar disorder (Benes et al. 2001; Rajkowska et al. 2001). Pathology
of layer II GABAergic neurons in bipolar disorder was confirmed by a study using an
antibody to calbindin (Cotter et al. 2002a). Calbindin-positive neurons are a subset of
GABA neurons. A decrease in calbindin-positive neuron density was also found in
the dorsolateral prefrontal and occipital cortices in MDD (Maciag et al. 2010; Rajkowska et al. 2007). A reduction in GABA cell density coincides with clinical evidence of
decreased levels of cortical GABA in MDD (Hasler et al. 2007; Sanacora et al. 2000).
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Glutamatergic, in addition to GABAergic, neuron pathology has been detected in
mood disorders. The density of pyramidal neurons was decreased in cortical layers III,
V, and VI of the orbitofrontal cortex and in deep sublayer Vb of the anterior cingulate
cortex in mood disorders (Gittins and Harrison 2011; Rajkowska et al. 2005). There
may be a deficit in glutamatergic neurotransmission in mood disorders, as pyramidal
neurons of layers III, V, and VI use glutamate as a neurotransmitter. The role of the
glutamatergic system in the pathophysiology and treatment of mood disorders is fur
ther supported by postmortem, clinical, and preclinical studies (e.g., Deschwanden et
al. 2011; Duman et al. 2019; Feyissa et al. 2009; Kadriu et al. 2019; Kugaya and Sana
cora 2005). Interestingly, the drug ketamine, an antagonist at glutamatergic N-methyl-
D-aspartate receptors, produces a rapid antidepressant effect in people with treat-
ment-resistant MDD (Kadriu et al. 2019).
Pathology of cortical neurons in mood disorders coincides with a substantial reduction in the number of synapses. The density of dendritic spine synapses was
nearly halved in the dorsolateral prefrontal cortex in MDD, as determined by electron
microscopy (Kang et al. 2012). In both PET and functional MRI (fMRI) studies, both
synaptic density and functional connectivity were decreased in the dorsolateral prefrontal and anterior cingulate cortices in MDD (Holmes et al. 2019). Rodent models of
depression and stress have been used to examine synaptic structure and function, be
cause there is evidence of neuronal atrophy, reduced synaptic density, and cell loss
(reviewed in Duman and Aghajanian 2012).
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Hippocampus
Morphometric studies have examined the hippocampal formation in mood disorders.
In a detailed stereological estimation of the total number of neurons in all hippocampal
substructures, there were no significant changes in MDD (Cobb et al. 2013). However,
an increase in the density of pyramidal neurons with a longer duration of depression
may explain the reduction in hippocampal volume in imaging studies of MDD (Sheline et al. 1996). In a study of bipolar disorder, there was a decrease in the density and
size of nonpyramidal neurons in a hippocampal subregion (Benes et al. 1998).
Subcortical Structures
Morphometric studies in the hypothalamus, amygdala, and brain stem nuclei in
mood disorders reveal mixed and inconsistent findings—namely increases, de
creases, or no change in the cell number or density. For example, the numbers of specific populations of immunoreactive neurons in the hypothalamus were increased in
mood disorders (Purba et al. 1996; Raadsheer et al. 1994; Swaab et al. 1993), consistent
with activation of the hypothalamic-pituitary-adrenal (HPA) axis in some individuals
with depression (Holsboer et al. 1992). The number and density of serotonin-immunoreactive neurons were increased in the dorsal raphe of depressed subjects who died
by suicide compared with controls (Underwood et al. 1999). There was no difference
in the number of noradrenergic neurons in the locus coeruleus between MDD patients
and control subjects; however, there was a reduction in the level of noradrenergic
transporters on these neurons in subjects with MDD, suggesting a compensatory
downregulation of this transporter in response to an insufficient availability of norepinephrine at the synapse (Klimek et al. 1997). Finally, there were no changes in neuro-
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nal density or number of neurons in the amygdala in MDD or bipolar disorder
(Bowley et al. 2002; Rubinow et al. 2016).
Attempts to Reverse Cell Pathology With
Antidepressants and Mood Stabilizers
It remains to be determined whether cellular changes found in mood disorders represent the cause or the consequence of the disease, or are a response to medication (or
some combination of all of these mechanisms). Because studies of postmortem tissue
are cross-sectional rather than longitudinal, identifying a temporal sequence of cell
pathology remains elusive. However, there is strong evidence from an animal model
of stress showing that loss of glial cells in the prefrontal cortex induces depressionlike behaviors (Banasr and Duman 2008). Interestingly, unpredictable stress-induced
glial loss can be reversed by riluzole, a glutamate-modulating drug (Banasr et al.
2010). Earlier stress-related models of depression revealed that loss of glial cells and
diminished neurogenesis in the hippocampus and medial prefrontal cortex were re
versed by treatment with the antidepressant fluoxetine (Czéh and Nagy 2018; Malberg and Duman 2003). Moreover, it was reported that antidepressant therapies act
directly on astrocytes, modifying their function and morphology (Czéh and Nagy
2018; Zhao et al. 2018). In addition to antidepressant drug treatment, electroconvulsive therapy stimulates the proliferation of hippocampal progenitor cells (Madsen et
al. 2000; Scott et al. 2000). The mood stabilizer lithium can also increase hippocampal
neurogenesis in mice (Chen et al. 2000) and the number of mature neurons and glial
cells in the hippocampus (Rajkowska et al. 2016). Hippocampal neurogenesis also occurs in the hippocampus of nonhuman primates and humans and is affected by stress
and possibly depression in humans. In monkeys, stress-induced depression-like be
havior and reduced hippocampal neurogenesis are prevented by treatment with fluoxetine (Perera et al. 2011). In MDD, cellular changes in the hippocampus suggest less
neurogenesis (Boldrini et al. 2019). Subjects with MDD receiving antidepressant
drugs that are selective serotonin reuptake inhibitors had more neural progenitor
cells in the hippocampus than untreated MDD subjects and control subjects (Boldrini
et al. 2012). Thus, at least some of the glial and neuronal cell loss or atrophy observed
in mood disorders may be prevented or reversed by antidepressant or mood-stabilizing treatments.
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Conclusion: Functional Consequences of Cell
Pathology in Mood Disorders
Alterations in the cell number, density, and size of specific populations of brain cells,
as well as their molecular pathology, may account for the brain dysfunction observed
in MDD and bipolar disorder. For example, deficits in astrocytes may account for the
glutamatergic system dysfunction observed in imaging and postmortem studies in
MDD. Pathology of oligodendrocytes and myelin-related genes may underlie the disturbed connectivity of frontolimbic brain regions reported using diffusion tensor im-
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