Psychiatry Research 128 (2004) 1 – 7

www.elsevier.com/locate/psychres

Microtubule-associated protein MAP2 expression in olfactory bulb

in schizophrenia
Lise Rioux *, Delta Ruscheinsky, Steven Edward Arnold
Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
Received 13 October 2003; received in revised form 26 March 2004; accepted 22 May 2004

Abstract

Previous studies have described alterations in presynaptic and postsynaptic elements in various parts of the CNS in
schizophrenia, which may, at least in part, be due to abnormalities in neurodevelopmental processes. The olfactory bulb (OB) is
a unique CNS area for examining synaptic development and plasticity in schizophrenia because it undergoes continuous
reinnervation throughout life. Moreover, olfactory deficits and reduced OB volume have been observed in schizophrenia. We
investigated the expression in the OB of the microtubule-associated protein MAP2, which has been shown to be abnormally
expressed in the hippocampal region in schizophrenia. In both developing and mature neurons, MAP2 is an important structural
component of dendrites and participates in the modification of synaptic organization. We used immunocytochemistry with
phosphoepitope-specific and phosphorylation-state-independent antibodies to examine MAP2 expression in the glomerular
layer of the OB in elderly subjects with chronic schizophrenia and controls. Phosphorylation-independent MAP2 expression
was significantly reduced in schizophrenia, while phosphorylated MAP2 expression did not differ between groups. These
results are consistent with faulty OB innervation in schizophrenia.
D 2004 Elsevier Ireland Ltd. All rights reserved.

Keywords: AP18; Glomerulus; Dendrite; Plasticity

1. Introduction are abnormal in schizophrenia (Moberg et al., 1999;

Psychophysical studies have documented deficits in
odor detection, identification, and memory in schizo-
phrenia (Moberg et al., 1999). Clinical neurobiological
studies have shown that the olfactory bulb (OB) is
smaller and that olfactory evoked response potentials
* Corresponding author. Present address: Laboratory for Bio-
Imaging and Anatomical Informatics, Department of Neurobiology
and Anatomy, Drexel University College of Medicine, 2900 Queen
Lane, Philadelphia, PA 19129-1096, USA. Tel.: +1-215-991-8410;
fax: +1-215-843-9367.
E-mail address: lrioux@earthlink.net (L. Rioux).
Turetsky et al., 2000). Additionally, postmortem stud-
ies have described cellular and molecular abnormali-
ties in the olfactory epithelium (Arnold et al., 2001).
Given the mounting evidence for abnormal neuro-
development in schizophrenia, the OB provides a
valuable window into the cellular and molecular pro-
cesses of axon guidance, synaptogenesis and synaptic
plasticity that may go awry in schizophrenia (Arnold
and Rioux, 2001). Its value as a model system lies on
the fact that the OB undergoes continuous reinnerva-
tion throughout life as olfactory receptor neurons
(ORNs) in the neuroepithelium of the nose turn over
and send new axons to synapse with the glomeruli of

0165-1781/$ - see front matter D 2004 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.psychres.2004.05.022
2 L. Rioux et al. / Psychiatry Research 128 (2004) 1–7

the OB (Farbman, 1992). The development and ap-
pearance of glomeruli depend on influences imparted
by ingrowing axon terminals from the olfactory epi-
thelium (Philpot et al., 1997). Within the glomeruli, the
ORN axons make excitatory synapses with the den-
drites from mitral, tufted, and periglomerular neurons
of the OB (Kratskin, 1997) (Fig. 1). Additionally, the
intraglomerular circuit consists of the mitral and tufted
cell reciprocal dendrodendritic synapses with the peri-
glomerular cells.
Microtubule-associated protein 2 (MAP2) is a
neuron-specific cytoskeletal protein important for the
genesis and maintenance of dendrites (Matus, 1988).
In both developing and mature neurons, MAP2 par-
ticipates in the modification of synaptic and dendritic
morphology. MAP2 expression is dynamic, with
decreases of MAP2 mRNA and protein reported in
neurons following axonal injury (Svensson and Ald-
skogius, 1992a,b) and increases in MAP2 immunore-
activity observed with remodeling of dendrites after
denervation (Cáceres et al., 1988).
MAP2 has multiple phosphorylation sites recog-
nized by a variety of kinases and phosphatases (Walaas
and Nairn, 1989). MAP2 phosphorylation affects mi-
crotubule stability and growth, as well as MAP2’s
binding to neurofilaments and microfilaments (Hiro-
kawa et al., 1988; Audesirk et al., 1997). Neural
activity in hippocampus modifies dendritic organiza-
tion, in part, by regulating MAP2 phosphorylation
(Quinlan and Halpain, 1996). Experience-dependent

Fig. 1. Diagram of the olfactory bulb. The olfactory bulb (OB) receives input from the receptor neurons in the olfactory epithelium (OE) and
projects to the olfactory cortex (CTX). The olfactory bulb is composed of six layers (from inside out): AON, accessory olfactory nucleus; GCL,
granule cell layer; ML, mitral cell layer; EPL, external plexiform layer, GLM, glomerular layer; ON, olfactory nerve layer. The main neural
elements of the olfactory bulb include: GC, granule cell; MC, mitral cell; PG, periglomerular cell; TC, tufted cell. Abbreviations: olfactory tract
(OT); cribriform plate (CP).
 L. Rioux et al. / Psychiatry Research 128 (2004) 1–7
modifications in MAP2 phosphorylation also have
been observed in the developing OB (Philpot et al.,
1997).
While still controversial, MAP2 expression has
been reported to be altered in the subiculum (Roso-
klija et al., 2000; Arnold et al., 1991), entorhinal
cortex (Arnold et al., 1991;), hippocampus (Cotter et
al., 1997, 2000) and prefrontal cortex (Jones et al.,
2002) in schizophrenia, but no changes have been
observed in the cerebellum (Mukaetova-Ladinska et
al., 2002). Its expression has not been investigated in
the olfactory system. The present study used immu-
nocytochemistry to examine changes in MAP2 ex-
pression and phosphorylation in glomeruli of the OB
in schizophrenia.
2. Material and methods
Olfactory bulbs were obtained at autopsy from 11
subjects with schizophrenia and seven nonpsychiatric
control subjects comparable for age, sex and postmor-
tem interval (PMI) (Table 1). Schizophrenic subjects
had been elderly participants in a prospective clinico-
pathological studies program and diagnosed according
to DSM-III-R/DSM-IV criteria based on medical his-
tory, interviews with caregivers and direct clinical
examination (Arnold et al., 1995). All schizophrenia
subjects had required chronic hospitalization because
of severe symptomatology including cognitive and
functional impairment. Patients were excluded from
the study if they had additional psychiatric or neuro-
logic disorders predating or subsequent to the onset of
psychiatric symptoms. Written informed consent for
antemortem evaluation and autopsy was obtained from
Table 1
Clinical and demographic data on human subjects
Schizophrenic Control
Mean S.D. Range Mean S.D. Range
Age (years) 78.5 7.4 67 – 87 73.9
PMI (h) 12.2 6.3 6.5 – 30 11.8
Age of onset (years) 26.9 5.1 16 – 33 na
Duration (years) 52.7 7.7 39 – 60 na
CPZ1MO 175 351 0 – 800 na
CPZ1MO = antipsychotic dosage 1 month before death; S.D. = stan-
dard deviation; na = not available.
3
next of kin. Controls were seven non-neurologic sub-
jects obtained through the University of Pennsylvania’s
Center for Neurodegenerative Disease Research. While
none of them had undergone antemortem assessments,
a review of their clinical histories found no evidence of
psychiatric or neurological illness. At the time of death,
subjects were excluded because of anoxic injury or
extensive injury due to trauma, stroke, neoplasm,
infection or toxins. Gross and microscopic diagnostic
neuropathological examinations were conducted in all
cases and were normal.
Olfactory bulbs were dissected at autopsy, fixed
in formalin (3.7% formaldehyde in 0.1 M Tris, 0.9 g/
l NaCl (TBS)) or ethanol (70% ethyl alcohol, 150
mM NaCl) for 24 h, paraffin-embedded and cut into
20-Am-thick sections. Mounted sections were labeled
with a phosphorylation-independent mouse monoclo-
nal antibody to MAP2, clone C, and a mouse
monoclonal phosphospecific antibody, AP18. Both
well-characterized antibodies specifically recognized
all isoforms of MAP2. AP18 recognized MAP2
containing a phosphorylated Serine 136 residue
(Riederer and Innocenti, 1992; Riederer et al.,
1995). Sections were deparaffinized, rehydrated and
then incubated for 30 min in 1% H2O2. After two
washes in TBS, sections were incubated in TBS
containing 4% normal horse serum (NHS) for 60
min at room temperature. The sections were then
incubated overnight at 4 jC in TBS containing 4%
NHS and AP18 (neat) or clone C (neat), rinsed three
times with TBS and incubated in biotinylated sec-
ondary antibody in TBS with 4% NHS (1:100,
BioGenex) for 1 h at room temperature. After three
rinses with TBS, they were incubated 1 h in strepta-
vidin –horseradish peroxidase (1:100, BioGenex) at
room temperature. After three more rinses, they were
incubated with the chromogen diaminobenzidine
(0.1% DAB in 0.1 M Tris, 0.01% triton, pH 7.3)
and 0.03% H2O2 for 6 min and rinsed twice with
water. Sections were then dehydrated, coverslipped,
and coded for blind analysis by one observer (D.R.).
A section incubated without primary antibody was
10.7 60 – 91 processed in parallel and served as a negative con-
6.0 4.0 – 21
na na
trol. All cases were included in a single, precisely
na na timed run. One section per case was used in this
na na study.
To determine the optical density (OD) of the DAB
reaction product in the glomeruli of OBs, we used
4 L. Rioux et al. / Psychiatry Research 128 (2004) 1–7
Brain 3.0 (Nissanov and McEachron, 1991) on a
Macintosh computer attached to a Leitz DMRB mi-
croscope (Leica) and Pulnix video camera. At the start
of each image capture session, the scope illumination
was adjusted to a standard level using a blank slide.
To correct for unevenness in background illumination
and non-square pixels, shading correction and aspect
ratio correction were also performed on each captured
image. A slide-mounted OD step tablet was imaged
and a calibration curve generated. OD of negative
control slides served as background OD. For each OB,
a field of view was captured and all glomeruli
contained in it were delineated. The gray value for
each glomerulus was recorded and converted to an
OD value. Background OD was then subtracted from
that value. The number of glomeruli per section and
the area of each glomerulus were also determined.
Between-group differences for glomerular values,
age and PMI were assessed with the Mann-Whitney
U-test with an alpha level of 0.05 used to determine
significance. Gender differences between schizophre-
nia and control groups were assessed with the v2
test. We assessed effects of potentially confounding
factors, including age, PMI and antipsychotic med-
ication exposure, on glomerular MAP2 ODs with
Spearman Rank correlation analysis.
3. Results
MAP2-immunoreactive dendrites were abundant
in the glomeruli of both control and schizophrenia
subjects. No significant difference between groups
were observed in the number of glomeruli per section
identified with AP18 (Mann – Whitney, U = 31,
n = 18, P = 0.70) or clone C (Mann – Whitney,
U = 30.5, n = 18, P = 0.66). The mean number of
glomeruli per section was 25.86 (S.D. 20.78) glo-
meruli (AP-18) and 12.86 (S.D. 8.19) glomeruli
(clone C) for controls and 22.82 (S.D. 18.87) glo-
meruli (AP-18) and 10.91 (7.94) glomeruli (clone C)
for schizophrenia subjects. There was also no differ-
ence in the mean cross-sectional areas of glomeruli
labeled with AP18 (Mann – Whitney, U = 35, n = 18,
P = 0.75) or clone C (Mann – Whitney, U = 38, n = 18,
P = 0.96). The mean area of the glomeruli was 0.012
(S.D. 0.005) mm2 (AP-18) and 0.014 (S.D. 0.006)
mm2 (clone C) for controls and 0.017 (S.D. 0.015)
mm2 (AP-18) and 0.012 (S.D. 0.04) mm2 (clone C)
for schizophrenia subjects. OD values were reduced
in schizophrenia subjects compared with controls for
phosphorylation-independent (PI) MAP2 using the
MAP2 antibody clone C (Mann – Whitney, U = 15,
n = 18, P = 0.03) while the difference for phosphory-
lated (P) MAP2 using AP18 was less in schizophre-
nia, but did not reach significance (Mann –Whitney,
U = 22, n = 18, P = 0.14) (Fig. 2).
There were no between-group differences for age
(Mann – Whitney, U = 28, n = 18, P = 0.34), sex
(v2 = 0.51, n = 18, P = 0.47) or PMI (Mann –Whitney,
U = 37, n = 18, P = 0.89). Within the control group,
there was no correlation between glomerular PI
MAP2 OD and age (Z = 1.6, P = 0.12) or PMI
(Z = 1.5, P = 0.14). There was no correlation either
between glomerular P MAP2 OD and age (Z = 0.5,
P = 0.60) or PMI (Z = 0.5, P = 0.64) in this group.
Within the schizophrenia group, there was no corre-
lation between glomerular PI MAP2 OD and age
(Z = 0.05, P = 0.96), PMI (Z = 1.8, P = 0.07) or anti-
psychotic medication dose (Z = 0.14, P = 0.89). Simi-
larly, there was no correlation between glomerular P
MAP2 OD and age (Z = 0.2, P = 0.52), PMI (Z = 1.9,
P = 0.06), or antipsychotic medication dose (Z = 0.14,
P = 0.89) in this same group.
Fig. 2. Scatterplot of OD values for phosphorylated MAP2 (AP18)
and total MAP2 (clone C) immunoreactivity from control (Co) and
schizophrenia (Sz) subjects. Bars represent mean OD for each
group. *indicates P < 0.05 when compared with control.
 L. Rioux et al. / Psychiatry Research 128 (2004) 1–7
4. Discussion
The present study relies on optical density mea-
surement to evaluate the relative concentration of
immunolabeled MAP2 in postmortem OB. It shows
that schizophrenia is associated with a change in
MAP2 expression in the OB using an antibody that
recognizes MAP2 in a phosphorylation-independent
state. Our results also indicate a trend toward a
reduction of phosphorylated MAP2.
Optical densitometry allows rapid, objective and
automatic evaluation of immunohistochemical label
intensity. The use of this method for quantitative
analysis requires that the various steps in processing
and analysis be standardized, from the histological
treatments to image analysis. Even then, concerns
exist that this method of quantification may not
reflect the amount of a specific protein in the brain
sections. This immunohistochemical procedure in-
volving DAB as the chromogen leads to the forma-
tion of antigen, primary antibody, secondary
biotinylated antibody, avidin-biotin-peroxidase, and
DAB in which each step of the processing can react
nonlinearly. This nonlinearity is thought to be the
source of significant variation in the evaluation of the
relative concentration of an immunolabeled protein
across tissue sections. However, a recent study has
shown that the measure of OD of an immunolabeled
protein using DAB as a chromogen is in fact pro-
portional to its concentration in a tissue section as
long as the range of OD measured in the tissue falls
within the linear range of the OD calibration curve
(Rieux et al., 2002).
Is the observed reduction in MAP2 expression in
the OB related to the disease process? With increas-
ing postmortem interval, MAP dendritic staining has
been shown to diminish and be replaced by neuronal
staining (Schwad et al., 1994). However, since both
experimental groups had similar postmortem inter-
vals and there was no significant correlation be-
tween MAP2 levels and PMIs for either the control
or schizophrenia groups, a reduction in MAP2
expression is likely to represent a disease-related
change.
The observed MAP2 reduction could result from
reduction of dendritic arborization in the glomeruli or
from a decrease in the amount of MAP2 per glomer-
ular dendrite. One consequence of the ongoing normal
5
neurogenesis of ORNs in the olfactory epithelium is
that the OB is being continually reinnervated (Farb-
man, 1992). The OB neurons and dendrites that
synapse with the ingrowing ORN axons within the
glomeruli must, therefore, remain in a state of high
plasticity. MAP2 expression has complex functions
and its expression precedes the morphological appear-
ance of mature, functional dendrites (Moore et al.,
1998). A lower MAP2 expression in schizophrenia
may reflect reduced capacity for dendrogenesis by any
or all of the OB neurons extending their dendrites into
the glomeruli and connecting to ORN axons.
In a preliminary study, we screened a number of
other dendritic and spine markers in OB glomeruli,
including neurofilaments, Homer 1b and PSD 95, but
found no altered expression of these proteins in
schizophrenia subjects (Rioux et al., 2002). This
indicates that the density of dendrites in OB glomeruli
of schizophrenia subjects is similar to control values
and that the MAP2 deficit represents a molecule or
pathway specific abnormality.
The formation of abnormal synapses between the
ORNs and its OB targets could affect the expression
of MAP2 per dendrite. This would be compatible
with the dysregulation of olfactory receptor neuron
lineage that we have observed in the olfactory
epithelium of schizophrenia subjects (Arnold and
Rioux, 2001), which suggests the persistence of
ORNs in an immature state that may be incapable
of establishing mature synaptic connections (Verhaa-
gen et al., 1989).
A reduction in the activity of ORNs could also
affect the differentiation of dendrites in the neurons of
the OB (Matsutani and Yamamoto, 2000) and reduce
the expression of MAP2 in the glomeruli. However, a
reduction of ORN activity may more likely affect the
phosphorylation of MAP2 as previously shown (Phil-
pot et al., 1997).
Finally, the output neurons of the OB, the mitral
and tufted cells, synapse on neurons in the entorhinal
cortex, an area that also exhibits abnormalities in
schizophrenia (Arnold, 2000). Change in glomerular
MAP2 expression may therefore result from the
failure of the OB neurons to receive adequate trophic
support from their entorhinal targets (Shipley and
Ennis, 1996).
Postmortem interval has been shown to produce
MAP2 dephosphorylation, making it difficult to attri-
6 L. Rioux et al. / Psychiatry Research 128 (2004) 1–7
bute the findings of altered postmortem phosphory-
lated MAP2 levels to in vivo phosphorylation levels
(Schwab et al., 1994). Since both groups had similar
postmortem intervals and there was no significant
correlation between PMAP2 levels and PMIs for
either the control or the schizophrenia group, a change
in MAP2 phosphorylation could have represented a
disease state. While the reduction in glomerular phos-
phorylated MAP2 did not reach statistical signifi-
cance, this study does not completely exclude a
change in the phosphorylation state of MAP2. AP18
only recognizes MAP2 phosphorylated at Ser136, and
it is possible that additional phosphorylation state
changes occur at other residues (Walaas and Nairn,
1989). Moreover, due to the small sample size, it is
possible that a modest change in the level of phos-
phorylated MAP2 could not be detected. A final
possibility we cannot exclude is an increase in phos-
phorylation due to chronic neuroleptic treatment
(Lidow et al., 2001).
In conclusion, the decrease in MAP2 expression
in the OB extends previous findings in the hippo-
campal region, another highly plastic brain area
(Arnold et al., 1991; Rosoklija et al., 2000). We
speculate that at least one pathophysiological pro-
cess underlying schizophrenia is a disturbance in
the ability to successfully establish and remodel
functional synapses. If so, then these molecular –
structural abnormalities would be most evident in
areas of high plasticity. Dynamic areas of the CNS
such as the OB are important windows into these
processes.
Acknowledgements
MAP2 antibodies were gifts from Dr. Beat M.
Riederer. We want to thank Williams Bug and Dr.
Jonathan Nissanov for their comments on the
manuscript. We are grateful to Louise Bertrand for
her technical advice. This work was supported by NIH
grants MH00978, MH43880 and MH57401. We
express our gratitude to the patients, families, and
caregivers that participated in this work and our
appreciation to the residents and staff of the
University of Pennsylvania Schizophrenia Center,
Department of Psychiatry, and Department of Pathol-
ogy and Laboratory Medicine.
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