Introduction
Schizophrenia is a severe brain disorder
characterized by certain types of delusion, hallucination and
thought disorder (1,2). In addition to these aforementioned
symptoms that may be associated with enhanced brain activity,
schizophrenic patients develop additional symptoms of inhibition,
including avolition, alogia and affective flattening (2). Macroscopically, schizophrenic brains
exhibited enlargement of the ventricles and an overall reduction in
the temporal volume, while microscopical examination of the brain
revealed synaptic and spinal alterations, as well as gliosis, in
various brain areas, including hippocampal formation and the
prefrontal and the entorhinal cortices (3-9).
Additional studies have revealed increasing neuronal packaging
density, as well as decreased neuropil and smaller cell somata of
the pyramidal neurons in layer 3 in different brain areas,
including the primary and association auditory cortices, in
schizophrenia (9-12).
Dendritic spines perform a crucial role in regulating neuronal
excitability while receiving the vast majority of excitatory
synapses in the cortex (13,14).
Deficits in spines are related to impairments in the working
memory, attention, sensory-motor processing and sociability
(15-17).
Spine density has been reported to be significantly reduced in
neurons of the auditory cortex (12) and the basilar dendrites of deep
layer 3 pyramidal neurons (10),
but did not differ for pyramidal neurons in the superficial layer 3
or layers 5 and 6 of area 46 (10,18).
The spinal changes are thought to arise during development and are
probably related to disturbances of the mechanisms underlying the
formation and maintenance of spines.
Visual hallucinations are the second most common
type of hallucinations in schizophrenia (2). Previous studies demonstrated a
critical role for interneurons and cortical connectivity in the
generation of hallucinations (19,20).
At the same time, studies on the visual cortex of schizophrenic
brains have revealed impaired synaptic plasticity and reduced
gamma-aminobutyric acid (GABA) levels (21-23).
In the present study, the morphology of the
pyramidal cells and interneurons in the visual cortex from brains
of schizophrenic patients were examined. It was attempted to
describe any possible dendritic and spinal alterations compared to
normal control brains.
Patients and methods
Subjects
Brain samples were obtained from 10 neurologically
normal individuals with no history of neurological or psychiatric
illness, and 10 patients with schizophrenia, between January 2010
to December 2014 from the Department of Forensic Medicine and
Toxicology, at the Aristotle University of Thessaloniki, Greece.
All of the subjects were aged between 40 and 58 years
(Schizophrenia: Mean age, 48.6±5.7 years; 6 males and 4 females;
Controls: Mean age, 46.3±4.97 years; 7 males and 3 females) and
died from heart attack. The average autolysis time for all subjects
was 12±4 h. After their excision from the skull, all brains were
immersed in 10% neutral buffered formalin for at least 25 days. All
possible information on each subject regarding their previous
physical and illness history was obtained from autopsy reports and
medical records. The mean duration of the disease was 21±7 years
and they had all been prescribed antipsychotic medication. Written
informed consent regarding the use of the tissue for research
purposes was obtained from the relatives of each of the deceased.
The present study was performed according to the legislation of the
Greek Democracy (v.2,472/1997, 2,819/2000, 2,915/2001, 3,235/2004
and 3,471/2006) and the Committee for Research Deontology
Principles of the Aristotle University of Thessaloniki (24). The ethical approval number was
23/4/4521/2018. The brains were macroscopically and microscopically
examined by an independent neuropathologist and did not exhibit any
trauma, oedema or other pathology. Independent psychiatrists based
at the Psychiatric Hospital of Thessaloniki, made the diagnosis of
schizophrenia based on the criteria of the Diagnostic and
Statistical Manual of Mental Disorders Text Revision 5. All of the
patients exhibited visual hallucinations in their disease
history.
Tissue selection and processing
A tissue block measuring 10x5x20 mm was excised from
the primary visual cortex or V1 area (calcarine sulcus) (25) (Fig.
1A). The primary visual cortex may be easily recognized by a
band of myelinated axons that run parallel to the surface (line of
Gennari; Fig. 1B). The tissue
blocks were coded to prevent experimental bias and were processed
with the Golgi method and subjected to Nissl staining (26).
Cell selection criteria
Two neuronal types were selected for the present
study; the first one corresponds to the third cortical layer's
pyramidal neurons and the second to the inhibitory aspiny stellate
interneurons of the visual cortex. All neurons chosen for the study
were uniformly stained, there was no precipitated debris around
them and a good contrast between them and background were present
(27).
Golgi method
For silver impregnation, the specimens were
immediately immersed in a dilution of potassium dichromate (7 g of
potassium dichromate and 20 ml of formaldehyde solution 37% in 300
ml of tap water) at room temperature. They remained in that
solution for one week and were then immersed in an aqueous solution
of 1% silver nitrate, where they remained for one more week at a
temperature of 15˚C.
After fixation, the specimens were immersed in
paraffin and cut into thick sections ~120 µm thick, as neuronal
fields can be seen at their whole thickness at ~120 µm (25), using a Reichert slicing microtome. A
total of 5 randomly selected sections were obtained, with a 480 µm
distance between each sample. All of the specimens were examined
with an Axiostar Plus bright field microscope (Zeiss AG).
Nissl staining
Adjacent sections were cut at a thickness of 20 µm
and used for Nissl staining to evaluate the neuronal population and
define the depth of cortical layers and measure the thickness of
the cortex (25).
Neuronal tracing and dendritic
quantification
For each one of the 20 brains, 50 pyramidal cells
and 50 interneurons were selected. The neurons were then analyzed
based on the method described in a previous study by our group
(26).
Dendritic measures and Sholl
analysis
For the morphometric estimation, soma size, total
dendritic length, cell contraction, dendritic field asymmetry, the
total number of dendritic segments and bifurcations, and the length
and number of dendritic segments per order were measured.
Furthermore, the tracings were quantitatively analyzed with Fiji
software (version 2017; Fiji) and the Simple Neurite Tracer plugin
based on Sholl's method of concentric spheres (28,29).
Concentric spheres were drawn at intervals of 10 µm centred on the
cell bodies and dendritic intersections within each sphere were
counted (25).
Spine counts
The dendritic spine density was measured in 360
images, which were taken at a magnification of x1,000. Two
different investigators (FP and SC) independently counted visible
spines on three random segments of the dendritic tree of 20-30 µm
in length, the first one being on a first-order dendrite, the
second on a second-order dendrite and the third on a tertiary
branch (30).
Statistical analysis
Statistical analysis was performed using Student's
t-test based on 320 cells in R Studio (v. 4.04). To make sure that
the autolysis time did not affect dendritic measurements,
two-tailed Pearson product correlation analyses were performed
between all dependent measures and autolysis time (31). P<0.05 was considered to indicate
a statistically significant difference.
Results
Dendritic changes of pyramidal
neurons
Analysis with the Golgi impregnation technique
revealed a significant loss of distal dendritic segments, tortuous
branches and varicosities and an overall restriction of the
dendritic field in the schizophrenic brains compared to the normal
brains (Fig. 2A and B).
In the brains of schizophrenic subjects, the
dendritic field's total length was significantly decreased as
compared with that of normal subjects (Figs. 3A-D and 4A). A severe loss of distal dendritic
branches (quaternary) (Fig. 4B),
and a decrease in the number of terminal branches (Fig. 4C) and dendritic bifurcations were
also noted (Fig. 4D).
Compared to the normal controls, the branching ratio
was reduced in the schizophrenic group, and the average branch
length (Fig. 5A) and the maximum
branching order were likewise affected (Fig. 5B). As presented in Fig. 6, Sholl analysis indicated a
restriction of the dendritic field due to the loss of distal
branches, although the proximal ones in the pyramidal cells
remained intact (Fig. 6A). A small
amount of degenerated pyramidal neurons was also noted in the
schizophrenic brains, and none were identified in the control group
(Fig. 7).
Interneurons
Aspiny stellate interneurons of the visual cortex
from the schizophrenic brains exhibited a significant decrease of
the total dendritic length (Figs.
8A and B and 9A), severe loss of dendritic branches
(Fig. 9B) and a substantial
reduction of the number of terminal dendritic branches (Fig. 9C). The branching ratio was grossly
reduced, and the average branch length and the maximum branch order
were significantly affected (Fig.
10A and B). Sholl analysis of
interneurons indicated extensive loss of distal dendritic branches
and decline of the dendritic field density at a distance >100 µm
from the cell soma (Fig. 6B). The
number of bifurcations was markedly lower in schizophrenic brains
compared with controls (Fig.
9D).
Spinal changes
Pyramidal neurons exhibited a significant decrease
in spinal density, affecting mainly the distal dendritic segments,
while dystrophic and giant spines were also observed (Figs. 11 and 12).
Cortical thickness
The thickness of the primary visual cortex measured
in Nissl preparations was significantly different between the
groups of the study (Schizophrenia, 1,956±105 µm; Controls,
2,124±96 µm; P=0.023; Fig.
13).
Discussion
There remains a lack of consensus or set of
quantified patient characteristics in regards to Schizophrenia and
it has remained an enigma to neuropathologists (32). Accumulating evidence from
macroscopic and microscopic pathology has been provided in the last
20 years. The main macroscopic findings include a decrease in brain
weight (33-35),
brain length (36) and volume of
the cerebral hemispheres (37). An
additional enlargement of the lateral ventricles (36,37),
changes to limbic structures (38),
reduced size of temporal lobe structures (39-41),
decreased thalamic volume (34,42)
and enlarged basal ganglia (43)
have also been described. Certain findings regarding synaptic and
spinal pathology, cell orientation, neuronal density, neuronal
size, protein expression and neurotransmitter deficits have also
been consistently reported by numerous studies (6).
The majority of existing studies are focused on
hippocampal formation, the temporal lobe, prefrontal cortex and
basal ganglia. To the best of our knowledge, no previous study has
reported on the morphological changes of the pyramidal and stellate
neurons of the occipital lobe. In 1998, Garey et al
(44) reported decreased spinal
density on the pyramidal cells of lamina III from Brodmann areas 11
and 38 observed on Golgi staining, and in the same year, Woo et
al (45) indicated a selective
decrease of terminal branches in brodmann areas 9 and 46 chandelier
neurons.
In 1996, Roberts et al (46) revealed changes of the dendritic
spines at the striatum, and in the same year, Uranova et al
(47) described certain changes in
the postsynaptic density of axo-spinous synapses.
In addition, Dorph-Petersen et al (22) reported significantly decreased
neuronal volume with no significant reduction of the neuronal
density in the primary visual cortex of schizophrenic brains. These
results were confirmed by neuroimaging studies using voxel-based
morphometry, which reported a significant reduction in the
occipital lobe's overall volume with a decrease in grey matter in
schizophrenic patients (48-52).
In the present study, no significant changes in the
neuronal density of the primary visual cortex were obtained, but
the overall thickness of the primary visual cortex was
substantially decreased in schizophrenic brains, corroborating the
findings of the earlier study by Dorph-Petersen et al
(22). Golgi silver staining and 3D
reconstruction of neurons revealed several morphological changes on
both cortical aspiny interneurons and pyramidal cells. The total
neuronal volume was decreased in both populations. The aspiny
interneurons exhibited a severe restriction of their dendritic
field areas, along with a loss of distal and terminal dendritic
branches. Pyramidal neurons from lamina III similarly exhibited a
significant loss of terminal branches and substantially lower
dendritic spines, mainly on the distal branches.
Regarding the clinical significance of the present
results, visual hallucinations are amongst the most common symptoms
associated with increased brain activity in patients with
schizophrenia (48). They have been
correlated to GABA deficits and functional impairment of cortical
interneurons, as well as a disturbance of cortico-thalamic or
intracortical connections (19).
Furthermore, studies have revealed certain functional deficits of
the visual cortex in schizophrenic patients, including early-stage
visual processing, contrast sensitivity abnormalities, surround
suppression and motor processing disturbance (53,54).
Lamina III pyramidal neurons contribute to reception, elaboration
and transmission of the visual information to other cortical areas,
while the aspiny interneurons provide inhibitory control and
modulate the synchronized oscillations (55). Both neuronal populations are
critical for the integrity of the cortico-thalamic and
intracortical circuits. The loss of dendrites and dendritic spines
of both pyramidal cells and interneurons leads to a substantial
decrease of the synaptic contacts and a significant impairment of
the pyramidal-interneuronal connectivity, as well as of the
connections of the cells of the visual cortex with the neurons of
other cortical and subcortical areas, which may be implicated in
the modulation of the visual information (30,55).
Although other cortical areas beyond the primary visual cortex are
related to the production of visual hallucinations, the
interruption of connectivity of the primary visual cortex with
secondary visual, temporal and parietal areas may have a crucial
role in the pathophysiology of visual hallucinations and other
functional deficits of the visual cortex in schizophrenia.
To the best of our knowledge, the present study was
the first to describe the morphological alterations in pyramidal
and spinal stellate neurons on the primary visual cortex in
patients with schizophrenia. The results may provide novel insights
into the brain changes exhibited by patients with schizophrenia. It
may be concluded that the present observations may be related to
certain clinical phenomena associated with the visual cortex
usually encountered in schizophrenia.
Acknowledgements
Not applicable.
Funding
Funding: No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current
study are available from the corresponding author on reasonable
request.
Authors' contributions
IM prepared the manuscript and supervised the data
collection and analysis. FP, SC, EK and DK collected and analyzed
the data, and prepared the specimens. AC, ACI, RD and CT prepared
the manuscript and analyzed the data. SN, VC and SB made
substantial contributions to conception and design, acquisition of
data and analysis and interpretation of data. IM and SB confirm the
authenticity of all the raw data. All authors have read and
approved the final manuscript.
Ethics approval and consent to
participate
The present study was performed according to the
legislation of the Greek Democracy (v.2,472/1997, 2,819/2000,
2,915/2001, 3,235/2004 and 3,471/2006) and the Committee for
Research Deontology Principles of the Aristotle University of
Thessaloniki (24) (approval no.
23/4/4521/2018). Written informed consent was obtained from
relatives.
Patient consent for publication
For each of the patients and controls, and written
informed consent was obtained from their relatives and power of
attorneys regarding the publication of data and associated
images.
Competing interests
The authors declare that they have no competing
interests.
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