Directory UMM :Data Elmu:jurnal:B:Biological Psichatry:Vol48.Issue7.2000:

Cortical Bcl-2 Protein Expression and Apoptotic
Regulation in Schizophrenia
L. Fredrik Jarskog, John H. Gilmore, Elzbieta S. Selinger, and
Jeffrey A. Lieberman
Background: The etiology of schizophrenia remains unknown; however, a role for apoptosis has been hypothesized. Bcl-2 is a potent inhibitor of apoptosis and also
exerts neurotrophic activity in the central nervous system
(CNS). Bcl-2 expression is increased in the CNS of several
neurodegenerative disorders. Given that schizophrenia
has certain features of a limited neurodegenerative disorder, it was hypothesized that cortical Bcl-2 expression is
increased in schizophrenia.
Methods: Postmortem temporal cortex was obtained from
the Stanley Foundation Neuropathology Consortium with
matched control, schizophrenic, bipolar, and depressed
subjects. Bcl-2 protein was measured by enzyme-linked
immunoassay (ELISA) and Western blot. Primary analysis
was limited to schizophrenia versus control subjects.
Results: The ELISA demonstrated 25% less Bcl-2 protein
in schizophrenia (p 5 .046), supported by Western blot
results. A secondary analysis of schizophrenic and bipolar
subjects revealed twofold higher mean Bcl-2 in antipsychotic-treated versus neuroleptic-naive subjects.
Conclusions: Contrary to our hypothesis, cortical Bcl-2

was reduced in schizophrenia. This supports the notion
that schizophrenia is not a classic neurodegenerative
disorder; however, less Bcl-2 protein may signal neuronal
vulnerability to proapoptotic stimuli and to neuronal
atrophy. Also, the association between neuroleptic exposure and higher Bcl-2 levels could underlie the favorable
long-term outcomes of patients who receive maintenance
antipsychotic treatment. Biol Psychiatry 2000;48:
641– 650 © 2000 Society of Biological Psychiatry
Key Words: Bcl-2, schizophrenia, apoptosis, neurodegeneration, neurodevelopment, neuroprotection

From the Departments of Psychiatry (LFJ, JHG, ESS, JAL), Pharmacology (JAL),
and Radiology (JAL) and UNC Mental Health and Neuroscience Clinical
Research Center (LFJ, JHG, JAL), University of North Carolina School of
Medicine, Chapel Hill.
Address reprint requests to L. Fredrik Jarskog, M.D., University of North Carolina,
Department of Psychiatry, CB# 7160, Chapel Hill NC 27599.
Received March 27, 2000; revised June 29, 2000; accepted July 6, 2000.

© 2000 Society of Biological Psychiatry

Introduction

S

chizophrenia is a complex neuropsychiatric disorder
for which the etiology has remained stubbornly elusive. The neurodevelopmental hypothesis states that
schizophrenia is acquired through early-life neurobiological insults that produce permanent brain deficits, manifesting as psychosis in early adulthood (Weinberger
1987); however, a neurodegenerative hypothesis has also
been proposed, primarily based on clinical grounds, given
the protracted period of symptomatic dormancy and the
progressive deterioration that frequently follows the first
episode of psychosis (Lieberman 1999; McGlashan 1988).
This is further supported by the progressive neurocognitive impairment found in schizophrenia (Bilder et al 1992),
particularly in elderly patients (Davidson et al 1995;
Purohit et al 1998). Given the extensive articulation of the
neurodevelopmental and neurodegenerative hypotheses, it
is notable that specific mechanisms by which developmental and degenerative processes could cause cytoarchitectural and neurochemical changes have received relatively
little attention. Previously, investigators have hypothesized a role for apoptosis in the pathophysiology of
schizophrenia, particularly as related to neurodevelopmental insults (Akbarian et al 1996; Catts and Catts 2000;
Margolis et al 1994; Woods 1998). We suggest that

limited neurodegeneration may occur in concert with a
neurodevelopmental disorder and that a dysregulation of
apoptosis could underlie both of these seemingly divergent
processes.
Apoptosis is a form of cell death that is dependent on
new gene expression. It occurs with hallmark morphologic
features including cell shrinkage, nuclear condensation,
and DNA strand breaks, followed by cellular fragmentation and phagocytosis by adjacent cells (Steller 1995). The
process is rapid and does not generate an inflammatory
response. Apoptosis occurs extensively in normal early
neurodevelopment (Oppenheim 1991); however, apoptotic
neurons also have been documented in adulthood in
certain neurodegenerative disorders such as Alzheimer’s
and Huntington’s diseases (Bredesen 1995; Dragunow et
al 1995). Apoptosis can be activated experimentally by a
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642

BIOL PSYCHIATRY
2000;48:641– 650

broad array of stimuli including ischemia, hypoxia, and
proinflammatory cytokines (Charriaut-Marlangue et al
1996; Thompson 1995). Interestingly, these stimuli have
also been implicated as neurodevelopmental insults associated with schizophrenia (Geddes and Lawrie 1995;
Gilmore and Jarskog 1997; Mednick et al 1988).
The molecular mechanisms underlying apoptosis have
recently become the focus of intense research. Members of
the Bcl-2 family of proteins are emerging as primary regulators of apoptosis (Adams and Cory 1998). The best characterized is Bcl-2, a membrane-bound 26 kD protein that
strongly inhibits apoptosis. It appears to exert its antiapoptotic function through homo- and heterodimerization with
other Bcl-2 family members (e.g., Bax and Bcl-xL) to
regulate the passage of oxidative mediators (e.g., cytochrome
c) through the mitochondrial membrane (Green and Reed
1998). As an antiapoptotic regulatory protein, Bcl-2 exerts a
powerful neuroprotective effect. Cells that overexpress Bcl-2
demonstrate considerable resistance to a variety of proapoptotic insults (Zhong et al 1993). Importantly, Bcl-2 also has a
neurotrophic property that appears to be independent of its
antiapoptotic function—it can promote dendritic branching

and produce regeneration of damaged central nervous system
(CNS) neurons (Chen et al 1997). Therefore, it is interesting
that those neurodegenerative disorders with evidence of
apoptotic neurons generally have altered Bcl-2 expression as
well. For example, Bcl-2 protein is upregulated in striatum of
Parkinson’s disease (Marshall et al 1997; Mogi et al 1996)
and also in frontal and temporal cortices of Alzheimer’s
disease (Kitamura et al 1998; Satou et al 1995). In addition,
Bcl-2 demonstrates developmental upregulation in human
frontal cortex across the life span, increasing from early
childhood into adulthood (Jarskog and Gilmore 2000). Both
in normal aging and in neurodegenerative disease, Bcl-2
upregulation is thought to represent a compensatory neuroprotective response (Satou et al 1995; Vyas et al 1997).
Although considerable neuropathologic evidence exists
to support a neurodevelopmental etiology in schizophrenia, some data also indicate progressive and deteriorative
changes that suggest a limited neurodegenerative process.
A selected review of data will follow, relating the potential
involvement of apoptosis to developmental and degenerative hypotheses.
Evidence for a neurodevelopmental process includes
neuroimaging studies that demonstrate increased ventricular size (reviewed by Lawrie and Abukmeil 1998),

smaller temporal lobes (Dauphinais et al 1990; Gur et al
1998; Suddath et al 1989) and generalized cortical reductions primarily affecting gray matter in schizophrenia
(Zipursky et al 1992, 1998). Because these volume
changes have been found even at the onset of psychosis, it
frequently has been hypothesized that they derived from
an early neurodevelopmental event. Considered indepen-

L.F. Jarskog et al

dently, the neuroimaging data would be consistent with a
role for apoptosis in schizophrenia, particularly because
evidence of inflammation and scarring is absent; however,
structural neuroimaging offers limited direct insight into
the mechanism of tissue loss. Postmortem studies are
somewhat more revealing, but they are also more conflicting (reviewed in Harrison 1999). Investigators have used
rigorous stereologic cell counting techniques and did not
find evidence of cortical cell loss (Pakkenberg 1993;
Selemon et al 1995); however, Selemon et al (1995)
acknowledged that neuronal loss in schizophrenic frontal
cortex could not definitively be ruled out. Nonetheless,

although cell numbers appeared unchanged, clear evidence
of neuronal atrophy was documented (Rajkowska et al
1998; Selemon et al 1995). On the other hand, significant
neuronal reductions have been found in the thalamus and
nucleus accumbens (Pakkenberg 1990; Young et al 2000).
This provides stronger evidence that apoptotic cell loss
may have occurred in these subcortical brain structures.
Another line of evidence implicating apoptosis in schizophrenia is the report of neuronal maldistribution in temporal cortex (Akbarian et al 1993) and prefrontal cortex
(Akbarian et al 1996). These authors argued that certain
neurons did not die at developmentally appropriate stages,
resulting in maldistribution. Finally, supporting the neuroimaging studies, postmortem investigations have not
demonstrated excess gliosis or other common markers of
neurodegeneration (Arnold et al 1998; Benes et al 1991;
Purohit et al 1998). Thus, neuropathologic evidence consistent with a neurodevelopmental etiology of schizophrenia also appears moderately supportive of a limited role
for apoptosis.
Evidence to support a neurodegenerative hypothesis is
provided by an increasing number of neuroimaging studies. Of particular note are recent studies that demonstrate
a progression of cortical brain volume loss and ventricular
enlargement in childhood onset and first-episode schizophrenia (DeLisi et al 1997; Gur et al 1998; Rapoport et al
1997, 1999) and ventricular enlargement in poor-outcome

adult schizophrenia (Davis et al 1998; Knoll et al 1998).
This data has yet to be robustly replicated, but it provides
preliminary evidence that tissue loss may occur both
during the early stages of psychosis and in more severe
forms of the illness, signaling the potential presence of a
limited neurodegenerative process. Although neuroimaging studies do not provide insight into underlying cellular
or molecular mechanisms, progressive tissue loss is consistent with apoptosis. Alternatively, given the neurotrophic effects of Bcl-2 and evidence for neuronal atrophy in
schizophrenic cortex as described above, these findings
could also indicate neuronal atrophy in the absence of cell
loss, possibly mediated through insufficient neuroprotection.

Bcl-2 Protein Expression in Schizophrenia

BIOL PSYCHIATRY
2000;48:641– 650

Table 1. Summary of Demographic Characteristics of Human
Temporal Cortex Specimens
Age
(years)

N Gender Ethnicity
Control

15

Schizophrenia 15
Bipolar
15
disorder
Major
15
depression

9M
6F
9M
6F
9M
6F

9M
6F

14 W
1 AA
13 W
2 As
14 W
1 AA
15 W

Postmortem
interval (hours) Brain pH

48.1 6 10.7

23.7 6 9.9

6.3 6 0.2

44.5 6 13.1

33.7 6 14.6

6.2 6 0.3

42.3 6 11.7

32.4 6 15.9

6.2 6 0.2

46.5 6 9.3

27.5 6 10.7

6.2 6 0.2

Age, postmortem interval, and brain pH are presented as mean 6 SD. These
variables were not significantly different by analysis of variance. M, male; F,
female; W, white; AA, African American; As, Asian.

In light of the relatively consistent findings of neuropathology in the temporal lobe including volume reduction
by MRI as well as the neurocognitive importance of this
brain region in schizophrenia, the current study was
designed to examine apoptotic regulation in schizophrenia
by assessing Bcl-2 expression in temporal cortex. Altered
regulation of Bcl-2 may provide insight into the nature of
the pathophysiology in schizophrenia. Because Bcl-2 protein has frequently been upregulated in neurodegenerative
disorders and schizophrenia has certain features consistent
with neurodegeneration, we tested the hypothesis that
Bcl-2 protein levels would be elevated in postmortem
temporal cortex in schizophrenia.

Methods and Materials
Postmortem Samples
This study was approved by the Institutional Review Board of
the University of North Carolina School of Medicine. Postmortem temporal cortex (Brodmann’s area 21) was obtained from 60
subjects from the Stanley Foundation Neuropathology Consortium (Bethesda, MD) as a set of control, schizophrenic, bipolar,
and depressed subjects, n 5 15 per group. Brains were collected
from four state medical examiners under supervision of the
Stanley Foundation using standardized protocols for tissue procurement and processing across all sites. Subjects over age 68
were excluded to avoid comorbid neurologic disorders. Two
senior psychiatrists established DSM-IV diagnoses using information from all available medical records and from family
interviews. Details regarding the subject selection, diagnostic
process, and tissue processing is described by Torrey et al
(2000). Samples were matched for age, gender, ethnicity, side of
brain, brain pH, and postmortem interval (PMI; Table 1). Table
2 presents demographic and clinical characteristics for individual
subjects, including cumulative antipsychotic medication exposure and medications at time of death. All samples were stored at
280°C until use. As a condition for supplying its brain tissue, the
Stanley Foundation requires that all diagnostic groups are studied; however, schizophrenia was the primary focus of this study.

643

All experiments and data collection were performed in a blinded
manner.

Tissue Homogenization
Tissue (100 –300 mg) was placed in 10 volumes of 10 mmol/L
HEPES buffer (pH 7.0) with 0.32 mol/L sucrose, 0.1 mmol/L
phenylmethylsulfonyl fluoride (PMSF), 10 mg/mL aprotinin, 5
mg/mL pepstatin A, 1 mmol/L benzamidine, 0.1 mmol/L benzethonium chloride. Samples were homogenized (PowerGen 125,
Fisher Scientific, Pittsburgh) on ice for 30 sec and sonicated
(Sonic Dismembrator 60, Fisher Scientific) for 10 sec at 10 mV.
Samples were centrifuged for 15 min at 3000 rpm and 4°C.
Supernatants were assayed for total protein by the BCA method
(Pierce, Rockford, IL). All chemicals were obtained from Sigma
(St. Louis).

Enzyme-Linked Immunoassay (ELISA)
Samples were assayed for Bcl-2 using a commercially available
ELISA kit (Endogen, Woburn, MA), using previously described
methods (Jarskog and Gilmore 2000). Briefly, 96-well microplates were precoated with a mouse monoclonal antihuman Bcl-2
antibody (Ab; Endogen), and samples (50 mL) were diluted 1:1
(vol/vol) with fluorescein isothiocyanate (FITC)-labeled secondary Ab and applied in triplicate. The plates were incubated for 2
hours at room temperature, washed, and then all wells received
horseradish peroxidase-labeled anti-FITC Ab. Following 30 min
incubation, plates were washed, and TMB/peroxide was added
for color development. The reaction was stopped with sulfuric
acid, and the optical density was measured at 450 nm using a
microplate reader (Vmax, Molecular Devices, Sunnyvale, CA).
A Bcl-2 standard curve was generated to quantitate the amount of
Bcl-2 in Units/mg total protein. One unit is defined as the amount
of Bcl-2 protein in 1000 lysed cells of an internal control cell line
(Endogen). Intra-assay coefficients of variance were ,9.3% and
the interassay coefficient of variance was 6.9%.

Semiquantitative Western Blot
Samples were separated on 12% Tris-glycine polyacrylamide gels
using a minicell electrophoresis unit (Xcell II, NOVEX, San Diego),
as previously described (Jarskog and Gilmore 2000). Equal amounts
of protein (30 mg) were boiled for 5 min in Tris-glycine SDS sample
buffer (NOVEX) and applied to the gels. Gels were run with a
low-range molecular weight ladder (Rainbow MW Marker, Amersham Pharmacia, Piscataway, NJ) and a Jurkat cell lysate (Transduction Laboratories, Lexington, KY) for Bcl-2 control. Separated
proteins were transferred to polyvinylidene difluoride (PVDF)
membranes (Immobilon-P, Millipore, MA) at 25 V for 2 hours, and
complete transfer was ascertained by staining duplicate gels with
Coomassie Blue and membranes with Ponceau S (data not shown).
Nonspecific protein binding was blocked for 1 hour with 5%
blocking reagent (ECL, Amersham Pharmacia) in 0.1% Tween TBS
(TBST). Membranes were incubated for 1 hour at 25°C with a
mouse monoclonal antihuman Bcl-2 primary Ab (1:500, Transduction Laboratories) followed by 1 hour incubation with a secondary
sheep antimouse HRP-labeled Ab (1:1000, ECL, Amersham Phar-

644

L.F. Jarskog et al

BIOL PSYCHIATRY
2000;48:641– 650

Table 2. Demographic and Clinical Characteristics of Individual Subjects in the Stanley Foundation Neuropathology Consortium
Subject no.

Diagnosis

Age/gen/ethnicity

Cause of death

PMI (hours)

Medications at time of death

Lifetime fluph. eq

Substance abuse history

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60

N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
SCZ, D
SCZ, U
SCZ, U
SCZ, P
SCZ, U
SCZ, U
SCZ, U
SCZ, U
SCZ, P
SCZ, U
SCZ, U
SCZ, P
SCZ, U
SCZ, P
SCZ, U
BD, P
BD, P
BD, P
BD, woP
BD, P
BD, woP
BD, P
BD, P
BD, P
BD, P
BD, P
BD, woP
BD, P
BD, P
BD, woP
MD
MD
MD
MD
MD
MD
MD
MD
MD
MD
MD
MD
MD
MD
MD

52/M/W
44/F/W
59/M/W
52/M/W
52/M/W
53/M/W
44/M/W
35/F/W
41/M/AA
42/M/W
35/F/W
68/F/W
58/M/W
29/F/W
57/F/W
30/F/W
52/M/W
30/M/W
62/F/As
60/F/W
60/M/W
32/M/W
31/M/W
58/F/W
25/M/W
44/M/W
44/M/W
56/F/As
35/M/W
49/F/W
25/F/W
48/F/W
37/F/W
54/M/W
30/M/W
30/M/W
57/M/W
34/M/W
48/M/W
31/M/W
30/M/W
50/F/AA
61/F/W
50/M/W
50/F/W
32/F/W
53/F/W
44/F/W
65/M/W
52/M/W
46/M/W
42/F/W
51/M/W
39/M/W
42/M/W
56/M/W
56/F/W
30/F/W
43/M/W
47/M/W

CPD
CPD
CPD
CPD
CPD
CPD
CPD
CPD
CPD
CPD
CPD
CPD
CPD
Accident
Accident
Suicide
CPD
CPD
Accident
CPD
Accident
Other
Suicide
CPD
Suicide
CPD
CPD
Suicide
CPD
CPD
Suicide
CPD
Suicide
Other
CPD
Suicide
CPD
Suicide
Suicide
Suicide
Suicide
Other
Suicide
Suicide
CPD
Suicide
Other
Suicide
CPD
CPD
Suicide
CPD
Suicide
Suicide
Suicide
CPD
CPD
Suicide
CPD
CPD

28
25
26
8
22
28
10
23
11
27
40
13
27
42
26
60
61
32
26
40
31
19
14
26
32
50
29
12
35
38
24
22
29
39
31
56
19
23
13
28
45
18
60
19
62
47
40
32
19
12
26
25
26
23
7
23
28
33
43
28

None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
Thx, Des
None
Ris, Tdz
None
None
Tdz, Ami
Clz
Clz
Hal, Dh
Ris, Par
Hal, Cbz, Fx, Cz, Bz
Clz, Cpz, Li
Hal, Li, Dh, CH
Clz, Cpz, Ma, Bz, Dh
Hal, Clz, Cz
Thx, Cbz, Li, Trz
Val, Ser, Cpx, Cbz
Li, Bup, Cz, Lz
Li, Cbz
Li, Clz
None
Hal, Dh
Ris, Val, Vfx
None
Hal, Trz, Trx
Val, Bup
None
Fx, Val
Val, Clz, Fz, Bz
Val, Cmi
Imi, Ami, Ntp, Cz
Li, Trz
Fx, Imi, Lz
Pht
None
Cz, Dh
Li, Fx
Nef, Hxz
None
None
Ser
Vfx, Bus, Az
Ntp, Az, Cmi
Tri
Fx, Nef

0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
6000
9000
50,000
50,000
0
80,000
15,000
4000
35,000
4000
100,000
130,000
150,000
50,000
. 200,000
7500
32,000
1200
2500
60,000
0
60,000
7000
200
30,000
0
12,000
40,000
60,000
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0

Alc(p)
None
None
None
None
Alc(p)
None
None
None
None
None
None
None
None
None
Cnb
None
None
None
None
None
Alc, Amp
None
Alc(p)
Alc(p)
None
Alc, Poly(p)
None
Poly
None
Alc
Alc, Met
None
Alc(p)
None
None
Alc(p)
Alc(p)
None
Poly
None
Cnb, Coc
None
None
None
None
Alc
None
None
None
None
None
Alc (p)
Alc, Amp
None
None
None
None
Alc
None

gen, gender; PMI (hours), postmortem interval in hours; Lifetime fluph. eq, estimated lifetime antipsychotics in fluphenazine milligram equivalents; N, normal control subject;
M, male; W, white; CPD, cardiopulmonary disease; Alc, alcohol; (p), past history of; F, female; AA, African American, SCZ, D, schizophrenia, disorganized; Thx, thiothixene; Des,
desipramine; Cnb, cannabis; SCZ, U, undifferentiated; Ris, risperidone; Tdz, thioridazine; SCZ, P, paranoid; As, Asian; Ami, amitriptyline; Clz, clozapine; Amp, amphetamine; Hal,
haloperidol; Dh, diphenhydramine; Par, paroxetine; Cbz, carbamazepine; Fx, fluoxetine; Cz, clonazepam; Bz, benztropine; Cpz, chlorpromazine; Li, lithium; poly, polysubstance;
CH, chloral hydrate; Ma, maprotiline; BD, P, bipolar disorder with psychotic features; Trz, trazadone; Val, valproate; Ser, sertraline; Cpx, chlorprothixene; Met, methadone; Bup,
buproprion; Lz, lorazepam; BP, woP, without psychotic features; Vfx, venlafaxine; Trx, trihexyphenidyl; Fz, flurazepam; Cmi, clomipramine; MD, major depression without
psychotic features; Imi, imipramine; Ntp, nortriptyline; Pht, phenytoin; Nef, nefazadone; Hxz, hydroxyzine; Bus, buspirone; Az, alprazolam; Tri, trimipramine.

Bcl-2 Protein Expression in Schizophrenia

645

BIOL PSYCHIATRY
2000;48:641– 650

test, with two-tailed p values considered significant at .05. The
following secondary analyses were also performed, given the
exploratory nature of this study:
1. Bcl-2 levels for all diagnostic groups were analyzed by
one-way analysis of variance (ANOVA), with significance
at p , .05.
2. A linear correlation analysis was performed between age
and Bcl-2 in the control group.
3. Bcl-2 levels were analyzed by gender across all samples
using Student t test and by gender and diagnosis using
two-way ANOVA.
4. Bcl-2 levels for schizophrenic and bipolar subjects were
compared on neuroleptic-naive versus neuroleptic-exposed status using a Student t test, with two-tailed p values
significant at p , .05.
5. A linear correlation analysis was performed in schizophrenia and bipolar disorder between lifetime fluphenazine
equivalents and Bcl-2 concentrations.
6. In bipolar disorder, Bcl-2 levels were compared on lithium
and valproic acid treatment status at time of death.

Figure 1. Quantitative Bcl-2 protein expression (U/mg total
protein) in temporal cortex (Brodmann’s area 21) in control and
schizophrenic (SCZ) subjects, measured by enzyme-linked immunoassay. Bcl-2 levels were significantly reduced by 25% in
schizophrenic subjects (21.9 6 2.8 U/mg, mean 6 SEM, n 5
15), as compared with control subjects (29.3 6 2.1 U/mg, n 5
15) by Student t test (*p 5 .046).

Results
macia). Membranes were developed using chemiluminescence
(ECL, Amersham Pharmacia), and the protein bands were detected
on radiographic film (Hyperfilm ECL, Amersham Pharmacia) after
30 to 120 sec exposure. Optical densitometry of Bcl-2 bands was
performed using NIH Image 1.62, with all measures falling in the
linear portion of the curve. Band densities were normalized to a
control applied to all gels. In addition, 10 to 80 mg of the control
sample were immunoblotted to ascertain that all samples fell within
the linear portion of the densitometric curve (data not shown).

Statistical Analysis
A priori, the primary analysis was limited to control versus
schizophrenic specimens, given our underlying hypothesis. Bcl-2
levels between these groups were compared using a Student t

Contrary to our hypothesis, ELISA demonstrated a 25%
reduction in mean Bcl-2 levels in the temporal cortex of
subjects with schizophrenia (21.9 6 2.8 Units/mg protein,
mean 6 SEM) compared with control subjects (29.3 6 2.1
Units/mg protein) by Student t test (p 5 .046; Figure 1 and
Table 3). These results provide quantitative evidence of
reduced Bcl-2 protein in subjects with schizophrenia.
Inspection of Figure 2 indicates that subjects with bipolar
disorder and major depression had lower mean Bcl-2
levels compared with control subjects (schizophrenia ,
bipolar , depressed); however, the overall ANOVA was
not significant. In the control group, Bcl-2 levels had a
nonsignificant positive correlation with age (R2 5 .0392,

Table 3. Enzyme-Linked Immunoassay Bcl-2 Levels by Diagnosis and Subject
Normal control subjects

Schizophrenic subjects

Subjects with bipolar disorder

Subjects with major depression

Subject No.

Bcl-2 U/mg

Subject No.

Bcl-2 U/mg

Subject No.

Bcl-2 U/mg

Subject No.

Bcl-2 U/mg

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15

18.2
28.4
27.9
42.1
42.0
44.3
25.0
28.7
29.2
24.2
15.2
28.9
27.2
32.3
25.8

16
17
18
19
20
21
22
23
24
25
26
27
28
29
30

18.5
36.3
17.0
28.9
12.7
46.7
18.0
17.2
10.8
21.7
33.6
8.2
24.9
9.1
25.6

31
32
33
34
35
36
37
38
39
40
41
42
43
44
45

35.2
7.7
24.2
33.2
18.1
8.3
23.6
31.3
14.0
34.7
4.5
32.2
31.3
24.1
23.6

46
47
48
49
50
51
52
53
54
55
56
57
58
59
60

16.7
27.0
9.0
37.2
25.5
9.7
25.7
34.8
19.7
33.4
29.1
13.0
27.1
29.1
27.1

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L.F. Jarskog et al

Figure 4. Representative Western blot of Bcl-2 protein expression in the temporal cortex from the Stanley Foundation brain
collection. An equal amount of total protein (30 mg) was added
to each lane. The transfer membrane was incubated with a
monoclonal antihuman Bcl-2 Ab. The bands shown migrated to
26 kd using molecular weight markers. Lane 1 contained Jurkat
cell lysate for Bcl-2 control. Other lanes comprised control
subjects (2 and 3), schizophrenic subjects (4 and 5), subjects with
bipolar disorder (6 and 7), and subjects with major depression (8
and 9).

Figure 2. Bcl-2 protein concentrations (U/mg protein) in temporal cortex across all diagnostic groups of Stanley Foundation
brain collection as measured by enzyme-linked immunoassay.
Mean 6 SEM Bcl-2 levels were 29.3 6 2.1 U/mg in control
subjects, 21.9 6 2.8 U/mg in schizophrenic (SCZ) subjects,
23.1 6 2.7 U/mg in subjects with bipolar disorder (BD), and
25.0 6 2.4 U/mg in subjects with major depression (MD); n 5
15 per group. Secondary analysis of variance across all groups
was not significant (p . .05).

p . .05). There was no evidence of gender differences
when analyzing by gender and diagnosis using two-way
ANOVA or across all samples using a Student t test.
Semiquantitative Western blotting in temporal cortex
confirmed the ELISA results. Bcl-2 protein was 34%

Figure 3. Bcl-2 protein levels in the temporal cortex across all
diagnostic groups of Stanley Foundation brain collection as
measured by semiquantitative Western blot. Bcl-2 bands were
measured using optical densitometry and data were normalized
to a control sample (defined as 1.00). Normalized mean optical
densities (OD) are presented as mean 6 SEM, with 1.80 6 0.29
in control samples, 1.18 6 0.19 in schizophrenic (SCZ) samples,
1.51 6 0.72 in bipolar disorder (BD) samples, and 1.56 6 0.28
in major depression (MD) samples; n 5 15 per group. Although
not quite significant (p 5 .09), the mean for SCZ was 34% lower
than the mean for control subjects.

lower in subjects with schizophrenia (Figures 3 and 4),
although this did not quite reach statistical significance
(p 5 .09). Taken together, the ELISA and Western blot
methodologies provide consistent evidence that Bcl-2
protein is reduced in schizophrenia.
When the schizophrenic and bipolar subjects were
combined and analyzed by neuroleptic-naive (n 5 4)
versus neuroleptic-treated (n 5 26) status, mean Bcl-2
levels in the treated group were 96% higher (p 5 .033)
than in the untreated group (Figure 5); however, among
neuroleptic-exposed subjects, Bcl-2 levels did not correlate with cumulative neuroleptic exposure (p . .05).
Among bipolar subjects, Bcl-2 levels were 29% higher in
lithium-treated patients, but this difference was not significant. Likewise, no significant difference emerged for
valproic acid in this group.

Figure 5. Bcl-2 protein concentrations by enzyme-linked immunoassay in bipolar and schizophrenic patients as analyzed on
exposure to antipsychotic medication. Patients treated with
antipsychotic medications had 96% higher Bcl-2 levels (24.2 6
2.0, mean 6 SEM, n 5 26) compared with neuroleptic-naive
patients (12.3 6 4.1, n 5 4). p 5 .033 by Student t test.

Bcl-2 Protein Expression in Schizophrenia

Discussion
This is the first study to demonstrate that the apoptoticregulatory protein Bcl-2 is reduced in the CNS in schizophrenia. Our results did not support the initial hypothesis
that Bcl-2 protein would be elevated as a reflection of a
neurodegenerative property of the illness, similar to elevations of Bcl-2 previously observed in the CNS of
individuals with Alzheimer’s or Parkinson’s disease. This
implies that if schizophrenia does encompass a neurodegenerative component, then the degenerative mechanism
differs substantially from classic neurodegeneration. The
reduction of Bcl-2 protein in schizophrenia has several
potential pathophysiologic implications. First, Bcl-2 is a
potent inhibitor of apoptosis, and a reduction of this
protein would suggest that the temporal cortex in schizophrenia is more vulnerable to proapoptotic stimuli,
whether those stimuli are products of normal physiology
and aging (Mrak et al 1997) or from a pathologic process.
Second, because Bcl-2 protein has neurotrophic properties
that are independent of apoptosis (Chen et al 1997), a
limited reduction of Bcl-2 could promote neuronal atrophy
and reduced axodendritic branching, without effects on
cell death. Thus, we propose that both apoptotic and
nonapoptotic mechanisms could subserve some of the
subtle neuropathologic findings in schizophrenia, mediated through reduced Bcl-2.
The etiology and timing of lower Bcl-2 protein in adult
schizophrenic brain is unclear. Although speculative, several possibilities emerge. First, Bcl-2 protein may be
constitutively underexpressed in schizophrenia. A genetically mediated underexpression of Bcl-2 may be less
likely, given the multisystem abnormalities and accelerated mortality demonstrated in Bcl-2 deficient mice (Veis
et al 1993). Overall, the minor physical anomalies and
subtle neuropathology in schizophrenia seem inconsistent
with such a mechanism. Alternatively, an environmental
stimulus during development could produce an enduring
yet limited downregulation of Bcl-2 expression. Such a
mechanism could potentially contribute to both early and
later brain development, thereby unifying neurodevelopmental and neurodegenerative hypotheses of schizophrenia; at this time, however, little is known of the effects of
early developmental insults on the long term effects on
Bcl-2 expression. Third, schizophrenia could be mediated
by an as yet unidentified neurodegenerative process that
induces the downregulation of Bcl-2 protein in adulthood.
In Alzheimer’s disease, Bcl-2 protein expression is upregulated overall, but there is evidence of selective Bcl-2
downregulation in neurofibrillary tangle-positive neurons
(Satou et al 1995). It seems that the pathophysiologic
process in schizophrenia must differ substantially from the
Alzheimer’s paradigm because schizophrenia does not

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2000;48:641– 650

647

have consistent evidence of large-scale neuronal loss or
robust gliosis, both hallmark features of Alzheimer’s
disease. A final consideration is that antipsychotic medications contribute to the downregulation of Bcl-2. This
possibility will be discussed in more depth below; however, our data suggests a correlation between higher Bcl-2
levels and antipsychotic exposure (Figure 5).
Bcl-2 protein may exert its effects in schizophrenia by
several specific mechanisms. First, Bcl-2 is strongly antiapoptotic, and overexpression of this protein is known to
confer resistance to neuronal cell death both in vitro and in
vivo by a broad spectrum of proapoptotic stimuli (Yang et
al 1998; Zhong et al 1993). Also, human cortical Bcl-2
expression is developmentally upregulated across the life
span (Jarskog and Gilmore 2000). In adulthood, upregulation may continue in response to age-related accumulation of higher oxidized protein levels, irreversible protein
glycation, lipofuscin, and DNA damage (Mrak et al 1997;
Vyas et al 1997). Therefore, a reduction of Bcl-2 protein
could increase the vulnerability of schizophrenic brain to
proapoptotic stimuli. Second, Bcl-2 has been found to
promote regeneration of damaged CNS neurons and enhance neurite outgrowth, revealing a growth-promoting
neurotrophic capacity that occurs independently of apoptosis (Chen et al 1997). Thus, as described earlier, lower
Bcl-2 levels in schizophrenia could lead to neuronal
atrophy and reduced dendritic branching. Studies that have
demonstrated higher neuronal density, reduced neuropil,
and reduced neuronal size in the absence of cell loss in
schizophrenic cortex are consistent with this mechanism
(Rajkowska et al 1998; Selemon et al 1995). In addition,
magnetic resonance spectroscopy studies have found
lower N-acetylaspartate levels in temporal and frontal
cortex in schizophrenia, thought to reflect reduced neuronal viability (Bertolino et al 1998; Cecil et al 1999).
Although such data does not prove Bcl-2 involvement, it is
also consistent and merits further study.
When subjects with schizophrenia and bipolar disorder
were combined and analyzed together, previous exposure
to antipsychotic medication was associated with higher
Bcl-2 levels in temporal cortex (Figure 5). This raises the
intriguing possibility that antipsychotic medications have
a neuroprotective function that is mediated through an
upregulation of Bcl-2 protein. Because of the small number of antipsychotic-naive patients in our sample (n 5 4),
this result needs to be interpreted with considerable
caution. Nevertheless, antipsychotic-mediated neuroprotection would lend support to the clinical observation that
antipsychotic medication treatment correlates with better
long-term outcome in chronic psychotic disorders (Wyatt
1991). Pharmacologic upregulation of Bcl-2 has recently
been demonstrated by lithium and valproic acid in rodent
frontal cortex (Chen et al 1999). Although subjects with

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2000;48:641– 650

bipolar disorder who were taking lithium at the time of
death also had numerically higher Bcl-2 levels (by 29%),
this difference was not statistically significant. The failure
to detect a difference may have been due to insufficient
power or to other, as yet uncharacterized confounding
variables. Future studies will be required to fully evaluate
the effects of psychiatric medications on Bcl-2 protein.
Several potential confounding variables could have affected the results of this study. First, it is possible that reduced
Bcl-2 protein was secondary to medication effects; however,
because a significant correlation emerged between a history
of antipsychotic treatment and higher Bcl-2 expression, it
suggests that reduced Bcl-2 in schizophrenia was not a result
of antipsychotic treatment. In fact, if antipsychotic medications do upregulate Bcl-2 protein, then such treatment may
have masked even lower baseline levels in the schizophrenic
subjects. A second variable relates to the known developmental upregulation of Bcl-2 expression, as documented
previously in human frontal cortex from infancy to adolescence and adulthood (Jarskog and Gilmore 2000). In our
study, we found a nonsignificant positive correlation between
age and Bcl-2 in the control group, which may have had
insufficient power to detect a correlation, or expression of
Bcl-2 in temporal cortex may differ from that of frontal
cortex. Nonetheless, because diagnostic groups were
matched for age, and age did not differ significantly between
groups (Table 1), aging-related changes would be unlikely to
account for lower Bcl-2 in schizophrenia. A third variable
relates to postmortem stability of Bcl-2 protein. We previously have determined that 24-hour postmortem stability of
Bcl-2 is high (,6% loss) using a rodent model designed to
approximate the human postmortem condition (Jarskog and
Gilmore 2000). Because mean PMIs in this study ranged
from 23.7 to 33.7 hours (Table 1) and did not differ
significantly among the four diagnostic groups, postmortem
degradation of Bcl-2 likely did not account for our findings.
Fourth, the Bcl-2 data in this study was quantified using
conventional methods based on mg total protein; however,
this method does not account for potential variations of total
protein per weight of brain tissue among subject groups.
Theoretically, if total protein per brain weight is higher in
schizophrenic compared with control cortex, then our findings of lower Bcl-2 in units per mg total protein could be
negated on a unit per brain weight basis. In fact, in a separate
experiment, schizophrenic subjects had 25% less total protein
per weight of brain compared with control subjects (data not
shown). This suggests that Bcl-2 protein per brain weight
may be even lower in schizophrenia than the 25% reduction
we measured in units per total protein. Finally, a number of
other confounding variables are possible, including diagnostic heterogeneity, history of substance abuse, and concurrent
medical illness. There are inherent limitations to ascertaining
clinical information in postmortem assessed subjects; how-

L.F. Jarskog et al

ever, given these limitations, the Stanley Foundation Neuropathology Consortium provides a unique opportunity to study
brain tissue in a relatively young group of subjects with
severe psychiatric disorders (Torrey et al 2000).
Interestingly, the data also revealed lower Bcl-2 levels by
ELISA in other psychiatric disorders, with reductions of 21%
in individuals with bipolar disorder and of 14% in individuals
with major depression compared with control subjects, although these changes did not reach statistical significance
(Figure 2). These trends were also observed in the Western
blot data (Figure 3). Neuroimaging studies in affective
disorders have revealed evidence of cortical volume reductions (Drevets et al 1997; Soares and Mann 1997). This
suggests a potential Bcl-2 mediated mechanism of neuronal
atrophy, loss, or both. Although speculative, the convergence
of downregulation in Bcl-2 protein across several disorders
could indicate a common downstream pathway in the pathophysiology of affective and psychotic disorders.
In summary, this study provides evidence that the pathophysiology of schizophrenia involves a dysregulation of the
apoptotic-regulatory protein Bcl-2. A reduction in Bcl-2
protein suggests that neuronal apoptosis, glial apoptosis, or
both may be altered through increased vulnerability to proapoptotic stimuli. In addition, Bcl-2 downregulation may
promote neuronal atrophy and reduced dendritic branching
through mechanisms unrelated to apoptosis. Unlike classic
neurodegenerative disorders such as Alzheimer’s disease,
specific markers of apoptotic cells have yet to be demonstrated in schizophrenia. Nonetheless, most evidence suggests that large-scale cell loss does not occur in schizophrenia, and small increases in neuronal apoptosis may remain
undetectable given the limitations of available techniques for
visualizing this process. Bcl-2 protein can begin to provide an
alternate source of information regarding the apoptotic balance of CNS neurons in schizophrenia. Given the complexity
of apoptotic protein regulation, a role for Bcl-2 in schizophrenia would likely occur in concert with other pro- and
antiapoptotic proteins and related factors that affect neuronal
viability. Further studies characterizing other Bcl-2 family
proteins and apoptosis-effector proteins (e.g., caspases) in
brain regions implicated in schizophrenia may help to clarify
the pathophysiology of this disorder. Ultimately, if a role for
apoptotic-regulatory proteins is established, then new avenues for intervention and treatment may emerge.

Supported by a National Alliance for Research on Schizophrenia and
Depression Young Investigator Award (LFJ) and National Institutes of
Health Center Grant No. MH-33127 (JAL).
Postmortem brains were donated by the Stanley Foundation Neuropathology Consortium courtesy of Drs. Llewellyn B. Bigelow, Juraj
Cervenak, Mary M. Herman, Thomas M. Hyde, Joel E. Kleinman, Jose´
D. Palta`n, Robert M. Post, E. Fuller Torrey, Maree J. Webster, and
Robert H. Yolken.

Bcl-2 Protein Expression in Schizophrenia

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