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Dysregulation of Olfactory Receptor Neuron Lineage in Schizophrenia
Steven E. Arnold, MD;
Li-Ying Han, MS;
Paul J. Moberg, PhD;
Bruce I. Turetsky, MD;
Raquel E. Gur, MD, PhD;
John Q. Trojanowski, MD, PhD;
Chang-Gyu Hahn, MD, PhD
Arch Gen Psychiatry. 2001;58:829-835.
ABSTRACT
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Background Growing evidence implicates abnormal neurodevelopment in schizophrenia.
While neuron birth and differentiation is largely completed by the end of
gestation, the olfactory epithelium (OE) is a unique part of the central nervous
system that undergoes regeneration throughout life, thus offering an opportunity
to investigate cellular and molecular events of neurogenesis and development
postmortem. We hypothesized that OE neurons exhibit deviant progress through
neurodevelopment in schizophrenia characterized by an increase in immature
neurons.
Methods Olfactory epithelium was removed at autopsy from 13 prospectively assessed
elderly subjects who had schizophrenia and 10 nonpsychiatric control subjects.
Sections were immunolabeled with antibodies that distinguish OE neurons in
different stages of development, including basal cells (low-affinity nerve
growth factor receptor, p75NGFR), postmitotic immature neurons (growth-associated
protein 43 [GAP43]), and mature olfactory receptor neurons (olfactory marker
protein). Absolute and relative densities of each cell type were determined.
Results We observed a significantly lower density of p75NGFR basal cells (37%)
in schizophrenia and increases in GAP43 + postmitotic immature neurons (316%)
and ratios of GAP43 + postmitotic immature neurons to p75NGFR + cells (665%)
and olfactory marker protein + mature neurons to p75NGFR + basal cells (328%).
Neuroleptic-free schizophrenia subjects exhibited the highest GAP43 + postmitotic
immature neuron values.
Conclusions Abnormal densities and ratios of OE neurons at different stages of development
indicate dysregulation of OE neuronal lineage in schizophrenia. This could
be because of intrinsic factors controlling differentiation or an inability
to gain trophic support from axonal targets in the olfactory bulb. While caution
is necessary in extrapolating developmental findings in mature OE to early
brain development, similarities in molecular events suggest that such studies
may be instructive.
INTRODUCTION
GROWING evidence from clinical and postmortem research implicates abnormal
neurodevelopment in the pathogenesis of schizophrenia. One of the field's
major challenges is to delineate abnormal neurodevelopmental processes that
could culminate in the disease at the cellular and molecular level. For the
neuropathologist, this would require either examination of brain tissue from
fetuses destined for schizophrenia (impossible to know) or study of neural
tissue in which there is ongoing neurogenesis from known patients with schizophrenia.
Neurons in the nonhuman primate and human brain are born, migrate, and assume
their mature phenotype in a complex and highly orchestrated process during
fetal development and the immediate postnatal period.1, 2, 3
By the time the clinical expression of schizophrenia is apparent, neurogenesis
and development is mostly complete. While there has recently been great interest
in several small populations of proliferating cerebral neurons in adulthood,4 their functional destiny is unknown. By and large,
the brain's neurons are morphologically static and molecularly homeostatic.
Thus, it would seem as if the opportunity to examine developing neurons in
schizophrenia is unavailable. However, components of the olfactory system,
that is, the olfactory epithelium (OE) and its synaptic targets in the olfactory
bulb provide an opportunity for a snapshot of morphologic and molecular neurodevelopmental
processes that are ongoing even in late life.
The olfactory system is a unique part of the central nervous system
where neurodevelopment robustly occurs throughout life.5
The OE continuously regenerates, with dividing stem and basal precursor cells
giving rise to immature neurons that migrate through the epithelium, differentiate
into mature olfactory receptor neurons (ORNs), send axons to reinnervate the
glomeruli of the olfactory bulb, and form new synapses with target neurons
there. As ORNs pass through different stages of development, they express
different proteins that can serve as molecular markers of the ORN's particular
stage of development.
The importance of examining the olfactory system in schizophrenia is
underscored by the marked impairments in olfaction that are present in the
disorder. Deficits have been reported in odor detection threshold sensitivity,6, 7 odor identification,8, 9, 10, 11, 12, 13, 14
and odor memory.13, 15 The pathoetiologies
of these deficits are unknown and could be caused by abnormalities in the
OE, the olfactory bulb, or central olfactory regions. In a recent meta-analysis
of olfaction research in schizophrenia, Moberg et al16
assessed the presence and relative levels of impairment in the 4 main olfactory
domains (identification, detection threshold sensitivity, discrimination,
and memory), and found "very large" effects of diagnosis for all 4. They also
examined possible influences of medication treatment, sex, and smoking on
effect sizes and found that these were not significant moderator variables.
Additionally, Moberg et al17, 18
have observed that olfactory impairments worsen with duration of illness,
independent of normal aging effects or other potential confounds. Most recently,
Turetsky et al19 documented a significant reduction
in olfactory bulb volumes with magnetic resonance imaging in subjects with
schizophrenia relative to healthy controls.
Given the many known cellular and molecular similarities in neurogenesis,
differentiation, and maturation between the OE and other regions of the central
nervous system,20, 21, 22, 23, 24, 25, 26, 27, 28
we propose that study of these events in the OE is instructive for understanding
putatively anomalous neurodevelopment in schizophrenia. We hypothesized that
OE exhibits deviant progress through neurodevelopmental events in schizophrenia.
In particular, we hypothesized an increase in immature neuronal forms that
are trying to establish synaptic connections with targets in the olfactory
bulb. In this study, we quantitatively characterized the cellular-molecular
phenotypic development within the ORN lineage in human OE tissues obtained
at autopsy from prospectively accrued and diagnosed individuals with schizophrenia
and matched control subjects. Cell type–specific antibodies directed
at the low-affinity nerve growth factor receptor (p75NGFR), postmitotic immature
neurons (growth-associated protein 43 [GAP43]), and olfactory marker protein
(OMP) were used to label ORN precursor cells, immature ORNs, and mature ORNs,
respectively (Figure 1). Examining
the densities and relative proportions of neurons at different stages of differentiation
within the ORN lineage provides insights into neuron turnover, birth, and
capacity for attaining a mature phenotype in the OE.
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Figure 1. Schematic illustration of adult
olfactory epithelium showing 4 cell types and their immunocytochemical profile.
Note that low-affinity p75 nerve growth factor receptor (p75NGFR), growth-associated
protein 43 (GAP43), and olfactory marker protein (OMP) are proteins that distinguish
different stages of the olfactory receptor neuron lineage. KER 8 indicates
keratin 8; MAP1B, microtubule-associated protein MAP1B (also called MAP5);
and NCAM, neural cell adhesion molecule.
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SUBJECTS, MATERIALS, AND METHODS
SUBJECTS
Autopsies were conducted on 13 elderly patients who had schizophrenia
and 10 age- and sex-compatible nonpsychiatric controls. All schizophrenia
subjects were prospectively accrued from 8 state hospitals in Pennsylvania
and were clinically assessed and diagnosed according to DSM-IV criteria by research psychiatrists (S.E.A., P.J.M., and R.E.G.)
of the University of Pennsylvania's Schizophrenia Mental Health Clinical Research
Center, Philadelphia, as previously described.29
This involved a standardized medical record review with recording of demographic
variables, presenting and subsequent symptoms, treatment history, medical
history, and laboratory and neuroimaging findings. Caregivers were interviewed
regarding clinical status and patients were examined with a systematic focus
on issues pertinent to confirming the diagnosis of schizophrenia and establishing
the presence of other psychiatric or medical disorders that would warrant
exclusion. Based on all information, diagnoses and inclusion were established
by research team consensus. Nonpsychiatric controls were obtained through
the University of Pennsylvania's Alzheimer Disease Center Core. While none
of these controls had antemortem assessments, review of clinical histories
found no evidence of prior major psychiatric illness. Presence or absence
of smoking history was documented by medical record review. If there was no
mention of smoking in the medical record but autopsy found lung emphysematous
changes, we considered that subject to have been a smoker.
The mean (SD) age of the schizophrenia sample was 78.2 (9.0) years and
included 6 males and 7 females. The mean age of the control sample was 70.0
(11.9) years, including 4 males and 6 females. Postmortem interval was identical
at 10.9 hours for schizophrenic (3.5) and control (5.9) samples. There were
no significant differences between groups for age (Mann-Whitney test21 = 35.5, P = .12), sex ( 21 = 0.09, P = .77), or postmortem interval
(Mann-Whitney test21 = 56.5, P = .60).
The mean age of onset for the schizophrenic sample was 23.5 (4.4) years, and
mean (SD) cumulative duration of hospitalization was 54.8 (9.35) years. All
schizophrenic cases had been treated with antipsychotic medications; however,
7 had not been receiving antipsychotic medication for at least 1 month and
4 had not been receiving antipsychotic medication for at least 1 year. Of
the 6 who were receiving antipsychotic medication 1 month prior to death,
the mean (SD) daily dosage, expressed as chlorpromazine milligram equivalents,
was 375 (206) mg. While none of the subjects had smoked within at least 2
years before death, 7 of the 13 schizophrenic cases and 3 of the 10 controls
had smoked previously.
All cases had gross and microscopic diagnostic neuropathologic examinations
at the time of death that included examination of multiple cortical and subcortical
regions. No neuropathologic abnormalities relevant to mental status were found
in the schizophrenic and nonpsychiatric groups, although minor abnormalities
were noted in 3 schizophrenic cases (2 with lacunar infarcts, 1 with a posterior
fossa meningioma); 1 control had Parkinson disease. Data analyses including
and excluding these cases were conducted with identical results.
IMMUNOHISTOCHEMISTRY FINDINGS
At autopsy, the OE, bony septae, and contiguous cribriform plate were
removed en bloc and fixed for 24 to 36 hours in 10% neutral-buffered formalin,
decalcified for 14 to 16 days in distilled water with sodium EDTA, sodium
hydroxide, and glycerol at pH 7.1 to 7.4.30, 31
Tissue blocks were then cut into coronal blocks, dehydrated in graded ethanols
to xylene isomers, and embedded in paraffin, as previously described.30 Ten-millimeter-thick serial sections were cut from
a central block of olfactory tissue in each case. Three double immunohistochemical
labeling procedures were conducted for each case, in duplicate, using antibodies:
(1) Me20.4 (1:10 for p75NGFR32), (2) growth-associated
protein GAP43 (1:1000, Sigma Chemical, St Louis, Mo33),
and (3) olfactory marker protein (OMP; 1:200034).
The p75NGFR antibody recognizes a receptor to trophic molecules and is selectively
expressed in the dividing precursor basal cells of the OE.30, 31
As basal cells commit to neuronal maturation, expression of p75NGFR ceases
and the postmitotic immature neurons begin to express GAP43. As these attain
a mature phenotype, they begin to express OMP and GAP43 diminishes.35, 36 Slides were double labeled for p75NGFR/GAP43,
p75NGFR/OMP, and GAP43/OMP. Immunohistochemistry studies were performed by
the peroxidase-antiperoxidase method, and used 3',3'-diaminobenzidine
as previously described.30, 37
In each instance, the 3',3'-diaminobenzidine chromogen solution
for the first antibody procedure included 2.5% nickel sulfate, while this
was excluded for the second antibody. This yielded a black reaction product
identifying the first antibody and brown for the second. All cases (schizophrenic
and control samples), as well as positive and negative control slides (with
and without primary antibody), were run simultaneously with precise timing
of reactions for each double immunohistochemical run.
QUANTITATIVE MICROSCOPY
We determined the densities of distinctly labeled cells at each of the
3 stages of development (p75NGFR + progenitor, GAP43 + immature, and OMP +
mature) as well as the relative proportions of cells to each other within
defined segments of the OE. In the adult olfactory mucosa, portions of olfactory
neuroepithelium (distinguished on the basis of their immunolabeling for neuron-specific
antigens) are irregularly interspersed with metaplastic respiratory epithelia
along superior portions of the nasal septum and turbinates.
Manual cell counting was performed on a personal computer (Macintosh;
Apple Computers, Cupertino, Calif) using the public-domain NIH Image program
(developed at the US National Institutes of Health and available on the Internet
at:
http://rsb.info.nih.gov/nih-image/) after codification for
blind analysis. Two closely adjacent double-labeled sections were used for
density determinations of each cell type (p75 NGFR basal cells, GAP43 immature
ORNs, OMP+ mature ORNs). Three to five 1-mm horizontal segments of OE adjacent
to the apex of the nasal cavity were delimited at low magnification (Figure 2A). After raising the magnification
to x400, all cells with visible nuclei of each immunolabeled cell type
within the delimited segment were manually counted, yielding a density measurement
(ie, the number of cells per millimeter in length). Because we counted all
cells within each segment, we did not need a random systematic sampling grid
or the optical fractionator. Similarly, because we counted only nucleated
cells, split cell artifact was minimized. The average densities of each cell
type in each case were calculated.
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Figure 2. Olfactory epithelium (OE). A,
Coronal section of nasal cavities (toluidine blue). Olfactory epithelium lines
the walls of left and right nasal cavities along turbinates (lateral walls)
and septum (medial walls). Segments for analysis were from the OE adjacent
to the apices of nasal cavities. Bar indicates 1 mm in part A. Nonpsychiatric
control (B) and schizophrenic case (C) OE was double-labeled for low-affinity
p75 nerve growth factor receptor (p75NGFR) + basal cells (brown) and immature
olfactory receptor neurons (ORN) expressing growth-associated protein 43 +
immature neurons (black or dark gray). Nonpsychiatric control (D) and schizophrenic
case (E) OE was double-labeled for p75NGFR + basal cells (brown) and olfactory
marker protein (black) (immunohistochemistry). BC indicates basal cell layer;
LP, lamina propria. Bar indicates 10 µm in part E.
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Relative densities of each cell type for each case were expressed as
a ratio, that is, [(GAP43 + cells)/(p75NGFR + cells)], [(OMP + cells)/(p75NGFR
+ cells)], and [(OMP + cells)/(GAP43 + cells)]. By using ratios of the densities
of different cell types, we create dimensionless indices of ORN lineage stage
representation in the OE within each case. This eliminates the potential methodological
problems associated with comparing cases that may have had differing degrees
of tissue shrinkage during autolysis, fixation, processing, or other nonspecific
factors, as well as variability in the thickness of the OE between and within
cases.
STATISTICAL ANALYSES
Between group differences were assessed using the Mann-Whitney test
for independent samples with an  level of .05 used to determine statistical
significance. This test was deemed most appropriate because of the sample
size and distribution of data. All tests were 2-tailed. In addition, we assessed
possible effects of age, history of smoking, postmortem interval, and antipsychotic
drug dose (expressed in daily chlorpromazine milligram equivalents 1 month
prior to death) on the neuropathologic indices using Mann-Whitney tests and/or
correlation analysis.
RESULTS
Double immunolabeling for p75NGFR/GAP43 and p75NGFR/OMP identified distinct
neuron populations at different stages of development (Figure 2). There was coexpression of GAP43 and OMP in many ORNs,
thus making a determination of a ratio between mature and immature ORNs difficult
in the GAP43/OMP slide series. Table 1 summarizes ORN subpopulation densities and ratios.
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Cellular Composition of Olfactory Epithelium*
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The density of p75NGFR + basal cells was significantly lower in schizophrenic
cases compared with controls (Figure 3).
In contrast, the density of GAP43 + ORNs was significantly increased by more
than 3-fold in the schizophrenic group. Olfactory marker protein + ORN density
was also somewhat increased in schizophrenic cases, but the difference was
not statistically significant.
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Figure 3. Scatterplots of cell density data
(number of cells per millimeter linear length of olfactory epithelium). N
indicates nonpsychiatric control subject (n = 10); S, schizophrenic case (n
= 13); p75NGFR, basal cells expressing the low-affinity p75 nerve growth factor
receptor; GAP43, immature olfactory receptor neurons expressing growth-associated
protein 43; and OMP, mature olfactory receptor neurons expressing olfactory
marker protein.
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In comparing the relative proportion of different developmental subpopulations
in the OE, we found that the ratio of GAP43 + immature neurons to p75NGFR
+ basal cells was significantly increased compared with the control group
by more than 6-fold. The mean [(OMP + neurons)/p75NGFR+] ratio was also significantly
increased. Given the substantial coexpression of GAP43 and OMP in postmitotic
neurons, a ratio of these cell types could not be directly determined in the
same section. Instead, the mean densities of each cell type in adjacent sections
were used to calculate a ratio of [OMP+/(GAP43 + ORNs)]. No between group
difference was observed.
There were no significant effects of age, postmortem interval, or smoking
history on the cellular composition of the OE in the total sample or the schizophrenic
or control subsamples examined separately. However, the ratio of GAP43 + ORNs
to p75NGFR + basal cells was significantly elevated in those patients who
had not been receiving antipsychotic medication for at least 1 month prior
to death (ratio = 3.99, SD = 1.07) compared with those who were receiving
antipsychotic medication (ratio = 1.08, SD = 0.92; Mann-Whitney test11 = 1.0, P = .01) in the setting of comparable
densities of p75NGFR + basal cells and modestly elevated GAP43 + ORNs and
OMP + ORNs.
COMMENT
In a previous study of the OE in schizophrenia,31
we examined the expression of cytoskeletal proteins, synaptophysin, glial
fibrillary acidic protein, protein gene product 9.5, and p75NGFR and found
the molecular phenotype of OE to be similar to that of controls. However,
that study was not quantitative and aside from p75NGFR, it did not assess
proteins that are selectively expressed at different stages of differentiation.
Here, our focus was the neurodevelopmental composition of the OE using antibodies
that were specific for neurons at different stages of maturation. We found
significant differences in the densities and ratios of immature neuronal forms
within the ORN lineage. The density and relative proportion of the immature
GAP43 + neurons is increased in the OE in schizophrenic cases while there
is a decrease in p75NGFR + basal cells and no difference in the density of
mature OMP + neurons. The finding that these effects were most notable in
patients who had not been receiving antipsychotic medication for at least
1 month prior to death, and some for longer than 1 year, suggests it is not
a confound of treatment.
Alterations in ORN lineage have been identified in various experimental
conditions where the OE was challenged with injury or synaptic targets in
the olfactory bulb were disrupted. For instance, in rodents, temporary destruction
of the OE (eg, with detergent) results in an increase in GAP43 as the OE reconstitutes
itself and reestablishes synaptic connections with the olfactory bulb.35 If the olfactory bulb is removed and axons emanating
from normal OE are unable to establish connections with their targets, there
is an arrest of the OE in an immature state as evidenced by a chronic increase
in GAP43 + neurons and a decrease in mature ORNs. Presumably this is because
of the ORN's inability to obtain trophic support from the olfactory bulb.
Our findings of an increase in the number and proportion of GAP43 + neurons
and a decrease in p75NGFR + basal cells in the OE could be because of an intrinsic
dysregulation of the differentiation of ORNs (ie, accelerated differentiation).
Alternatively, there may be an as yet undefined difficulty in establishing
healthy synaptic connections with the olfactory bulb that accelerates OE turnover.
Preliminary findings suggest this latter possibility.38
Caution must be heeded in interpreting our findings because of the small
sample size. Another consideration is that the advanced age of our subjects
and the chronicity of their illness may affect our findings and their generalization
to schizophrenia-at-large. However, the fact that we identify all stages of
the ORN lineage, even in later life, is supportive of the OE as a useful model
for neurodevelopmental studies. Furthermore, quantitative studies of the OE
in aged rodents have shown that the rate of cell proliferation decreases with
advancing age,39 thus, making our findings
of more immature ORNs in schizophrenia even more noteworthy.
Concerning our methods of quantitation, the sections and segments used
for counting were systematically chosen to be from a block in the center of
the rostral-caudal extent of the OE. As this was not strictly a random selection
nor a random systematic sampling throughout the extent of the OE, potential
bias may have been introduced.
Given the prevalence of smoking among schizophrenic subjects, we considered
this as another potential confound. Our own previous clinical psychophysical
studies, current analysis of postmortem data, and extensive review of the
literature indicate that this issue is of minimal concern for interpretation
of our data. In a recent meta-analysis of olfactory functioning in schizophrenia,
there was no significant relationship between smoking status and effect size
for olfactory impairments in schizophrenia.16
Furthermore, while, nonsmokers tend to outperform active smokers in olfactory
identification tasks in a dose-related manner, this effect is small and typically
resolves within 1 year of smoking cessation.40
None of our subjects were active smokers, although we cannot rule out exposure
to secondhand smoke. Directly related to possible smoking effects on OE, Feron
et al41 reported no differences between active
smokers and nonsmokers for attachment of OE biopsy cells to culture slides,
for in vitro behavior of outgrowing cells, for the mitotic ratio or cell death
ratio, or for cellular response to dopamine therapy.41
Finally, in our study, 7 of the 13 schizophrenic cases and 3 of the 10 controls
had a documented history of smoking (by clinical history or autopsy evidence
of emphysema). While we cannot be sure of any possible permanent residual
effects of a history of smoking on the OE, no differences between smokers
and nonsmokers were found for any study variable.
A potential limitation of a general nature concerns the relevance of
any findings in peripheral olfactory components (ie, OE) to neurobiological
processes occurring in the cerebrum. It is uncertain how similar the growth,
development, and behavior of ORNs are to hippocampal, frontal, or other telencephalic
neurons that are presumably abnormal in schizophrenia. However, the OE is
embryologically closely related to important limbic and neuroendocrine regions
of the brain.42, 43 It is derived
from the olfactory placode that also generates some cells that migrate to
the forebrain and that further has been proposed to have a morphogenetic and
inducing effect on the forebrain. In addition, while much attention has rightfully
focused on the neuroanatomy, neurochemistry, and functioning of limbic and
frontal regions as being important in schizophrenia,44, 45
there are also numerous data indicating neurobiological abnormalities throughout
the central nervous system.46, 47, 48, 49
The reason why the preponderant symptoms of schizophrenia may preferentially
involve higher cognitive, emotional, and social domains could be that the
cellular and molecular abnormalities of schizophrenia are most highly expressed
in brain regions of high plasticity, complexity, or prolonged maturation.
If this is true, then studying ongoing, highly dynamic neurodevelopmental
processes in the OE and its synaptic targets in the olfactory bulb may be
very instructive.
AUTHOR INFORMATION
Accepted for publication April 19, 2001.
This work was supported by grants MH55199 (Dr Arnold), MH59344 (Dr Arnold),
and MH43880 (Dr Gur) from the National Institute of Mental Health, Bethesda,
Md.
We also thank J. Kordower, PhD, for the gift of p75NGFR and F. L. Margolis,
PhD, for the gift of OMP.
We express our appreciation to the residents and staff of the University
of Pennsylvania Schizophrenia Center, Department of Psychiatry, and the Department
of Pathology and Laboratory Medicine, and to Warren Bilker, PhD, for biostatistical
consultation. Above all, we express our gratitude to the patients, families,
and caregivers at collaborating hospitals who participated in this work.
From the Laboratory for Cellular and Molecular Neuropathology, Center
for Neurobiology and Behavior (Drs Arnold and Hahn and Ms Han) and the Schizophrenia
Mental Health Clinical Research Center (Drs Arnold, Moberg, Turetsky, Gur,
and Trojanowski), and the Departments of Psychiatry and Pathology and Laboratory
Medicine (Dr Trojanowski), University of Pennsylvania, Philadelphia.
Corresponding author: Steven E. Arnold, MD, 142 Clinical Research
Bldg, 415 Curie Blvd, Philadelphia, PA 19104 (e-mail: sarnold{at}mail.med.upenn.edu).
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