Progress in Neuro-Psychopharmacology & Biological Psychiatry 29 (2005) 846 858

www.elsevier.com/locate/pnpbp

Review article

Apoptotic mechanisms in the pathophysiology of schizophrenia

L. Fredrik Jarskog*, Leisa A. Glantz, John H. Gilmore, Jeffrey A. Lieberman
Department of Psychiatry, Schizophrenia Research Center, University of North CarolinaChapel Hill, CB# 7160,
Chapel Hill, NC 27599-7160, USA
Accepted 1 March 2005
Available online 23 May 2005

Abstract
While schizophrenia is generally considered a neurodevelopmental disorder, evidence for progressive clinical deterioration and subtle
neurostructural changes following the onset of psychosis has led to the hypothesis that apoptosis may contribute to the pathophysiology of
schizophrenia. Apoptosis (a.k.a. programmed cell death) is a mechanism of cell death that operates in normal neurodevelopment and is
increasingly recognized for its role in diverse neuropathological conditions. Activation of apoptosis can lead to rapid and complete
elimination of neurons and glia in the central nervous system. Studies also show that in certain settings, pro-apoptotic triggers can lead to
non-lethal and localized apoptotic activity that produces neuritic and synaptic loss without causing cell death. Given that the neuropathology
of schizophrenia is subtle and includes reduced neuropil (especially synaptic elements), limited and often layer-specific reductions of
neurons, as well as neuroimaging data suggesting progressive loss of cortical gray matter in first-episode psychosis, a role for apoptosis in
schizophrenia appears plausible. Studies that have examined markers of apoptosis and levels of apoptotic regulatory proteins in postmortem
schizophrenia brain tissue will be reviewed in context of this hypothesis. Overall, the data seem to indicate a dysregulation of apoptosis in
several cortical regions in schizophrenia, including evidence that the apoptotic vulnerability is increased. Although the exact role of apoptosis
in schizophrenia remains uncertain, the potential involvement of non-lethal localized apoptosis is intriguing, especially in earlier stages of the
illness.
D 2005 Elsevier Inc. All rights reserved.
Keywords: Apoptosis; Bcl-2; Caspase; Neurodegeneration; Neurodevelopment; Schizophrenia

Contents
1.
2.

3.

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1. Underlying mechanism . . . . . . . . . . . . . . . . . . . . .
2.2. Synaptic apoptosis. . . . . . . . . . . . . . . . . . . . . . . .
Neuropathology of schizophrenia. . . . . . . . . . . . . . . . . . . .
3.1. Postmortem studies of neuronal and glial cell numbers . . . . .
3.2. Postmortem studies of neuropil and synaptic markers. . . . . .
3.3. Neuroimaging studies: evidence of progressive volume changes
3.4. Functional neuroimaging and spectroscopy . . . . . . . . . . .

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Abbreviations: BDNF, brain-derived neurotrophic factor; CNS, central nervous system; DSBs, double-stranded DNA breaks; ER, endoplasmic reticulum;
fMRI, functional MRI; GFAP, glial fibrillary acidic protein; IAP, inhibitor-of-apoptosis protein; MRI, magnetic resonance imaging; MRS, magnetic resonance
spectroscopy; NAA, N-acetylaspartate; NT-3, neurotrophin-3; NMDA, N-methyl-d-aspartate; PET, positron emission tomography; 1H, proton; SSBs, singlestranded DNA breaks; TUNEL, TdT-mediated dUTP nick end-labeling; U, units.
* Corresponding author. Tel.: +1 919 966 8035.
E-mail address: Jarskog@med.unc.edu (L.F. Jarskog).
0278-5846/$ - see front matter D 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.pnpbp.2005.03.010

L.F Jarskog et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 29 (2005) 846 858

4.

Apoptosis in schizophrenia . . . . . . . . .
4.1. Apoptotic regulatory proteins . . . .
4.2. DNA fragmentation . . . . . . . . .
4.3. Pro-apoptotic stress in schizophrenia
5. Conclusion . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . .

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1. Introduction
The neurodevelopmental hypothesis of schizophrenia has
substantially advanced our understanding of the important
roles that genes and environmental insults exert in the
etiology and pathophysiology of the disorder (McDonald
and Murray, 2000; Harrison and Weinberger, 2005).
However, the neurodevelopmental perspective does not
readily account for several important features of schizophrenia including the protracted period of symptomatic
dormancy between the putative insult and the emergence of
symptoms, the progressive clinical deterioration that affects
at least a subgroup of patients, and emerging evidence for
progressive neurostructural changes in certain ventricular
and cortical brain structures (Lieberman, 1999).
In an effort to identify a pathophysiological mechanism
that could account for the progressive elements of schizophrenia and dovetail with neurodevelopmental processes,
the potential role of apoptosis has increasingly been
considered (Margolis et al., 1994; Lewis and Lieberman,
2000; Berger et al., 2003). Apoptosis is a highly regulated
form of cell death that is often likened to cellular suicide.
Apoptosis is pervasive during early development of the
central nervous system (CNS) over half of all developing
neurons die by apoptosis (Burek and Oppenheim, 1996)
and it also serves to eliminate injured or diseased neurons
throughout life. Apoptosis occurs rapidly (an apoptotic cell
is typically cleared within 24 h) and proceeds without
incurring a gliotic response. Furthermore, although apoptosis is often thought of as a terminal event in a given cell, the
emerging concept of synaptic (a.k.a. neuritic) apoptosis
suggests that activation of apoptosis in neurons can be
localized to synapses or distal neurites without inducing
immediate neuronal death (Mattson et al., 1998). Given that
the neuropathology of schizophrenia includes evidence of
shorter dendrites, reduced neuropil, limited reductions in
neuronal and glial cell numbers, lack of gliosis, and in vivo
neuroimaging evidence of progressive gray matter loss early
in the disorder, a potential role for apoptosis appears
increasingly plausible.
This paper will provide an overview of apoptosis to
include the major apoptotic pathways and review the
evidence for localized synaptic apoptosis. A review of the
neuropathology of schizophrenia will target evidence for
neuronal and glial cell loss as well as reduced neuropil.
Studies of apoptosis in schizophrenia will be assessed in
context of the hypothesis that apoptotic mechanisms

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contribute to the neuropathology of schizophrenia. This

will include a discussion on the evidence for pro-apoptotic
triggers in schizophrenia in both early and late pathophysiological stages.

2. Apoptosis
2.1. Underlying mechanism
The cytomorphological features associated with apoptosis are distinctly different from necrosis, the other form of
cell death. Apoptosis is characterized by cell shrinkage,
membrane blebbing, chromatin condensation, DNA fragmentation, and cellular disintegration with phagocytosis
(Bredesen, 1995). Apoptosis occurs without inflammation
and typically requires the formation of new gene products to
proceed. The mechanism of apoptosis is focused on
regulating the activation of cysteine-dependent aspartatedirected proteases known as caspase proteins (Friedlander,
2003). Caspases have a very stringent cleavage requirement
for the carboxyl side of aspartate residues. Initiator caspases
(e.g. caspase-8, -9, and -10) are responsible for promoting
the cleavage of downstream effector caspases (e.g. caspase3, -6, and -7), and caspase-3 is the effector caspase most
often associated with apoptosis in the CNS (Yuan and
Yankner, 2000). Effector caspases are activated by cleavage
and active caspase-3 in turn cleaves a number of specific
structural and functional proteins, leading to the characteristic apoptotic morphology (Boatright and Salvesen, 2003).
At least three distinct mechanisms have been identified
that lead to caspase-3 activation: the mitochondrial (intrinsic) pathway, the death receptor (extrinsic) pathway and the
inflammatory (caspase-1-mediated) pathway, Fig 1. The
mitochondrial pathway regulates caspase activity through
mitochondrial release of cytochrome c. Cytochrome c forms
a complex with caspase-9 and the adaptor protein Apaf-1 to
produce an apoptosome. The apoptosome cleaves procaspase-3 into active caspase-3 that then begins the structural
breakdown of the cell (Adams and Cory, 2002). An
important upstream checkpoint for cytochrome c release
involves interactions of pro- and anti-apoptotic members of
the Bcl-2 family of proteins. These proteins interact through
dimerization in the mitochondrial membrane. The ratio of
specific pro-apoptotic (e.g. Bax, Bak, Bid, Bcl-XS) to antiapoptotic (e.g. Bcl-2, Bcl-XL) protein levels determines
whether a given pro-apoptotic stimulus will lead to

848

L.F Jarskog et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 29 (2005) 846 858

Fig. 1. Overview of the mitochondrial, death receptor and inflammatory pathways of apoptosis. The mitochondrial pathway involves the regulation of
mitochondrial cytochrome c (Cyto c) release by Bcl-2 family proteins (e.g. Bax, Bcl-2) in response to pro-apoptotic stimuli. Cyto c forms a complex with
Apaf-1 and procaspase-9 to form the apoptosome. This complex cleaves procaspase-3 into activated caspase-3, leading to cleavage of key functional and
structural proteins. The caspase cascade is modulated in part by inhibitor-of-apoptosis proteins (IAPs) that can inhibit caspase-9 and caspase-3. The death
receptor pathway involves TNFa or Fas ligand binding to the death receptor. Adaptor molecules in turn recruit procaspase-8 which undergoes autocatalytic
cleavage and then activates procaspase-3. Alternatively, activated caspase-8 can impact the mitochondrial pathway at an upstream level by promoting Baxmediated release of Cyto c via BID. Finally, the inflammatory pathway is initiated by cleavage of procaspase-1 into activated caspase-1. While caspase-1 is a
well-known activator of prointerleukin-1h, active caspase-1 can promote mitochondrial Cyto c release via BID.

mitochondrial cytochrome c release and caspase activation.

The Bax to Bcl-2 ratio represents a prototype for such
regulatory control with high Bax/Bcl-2 ratios promoting
apoptosis and low Bax/Bcl-2 ratios inhibiting apoptosis
(Oltvai et al., 1993). Importantly, Bcl-2 protein also has
neurotrophic properties that function independently of the
cell death mechanism. Overexpression of Bcl-2 can enhance
neurite outgrowth (Oh et al., 1996; Zhang et al., 1996) and
promote regeneration of severed CNS axons (Chen et al.,
1997), while Bcl-2 heterozygosity slows neuronal maturation (Middleton et al., 1998). Finally, the inhibitor-ofapoptosis protein (IAP) family represents a powerful
downstream inhibitory checkpoint of the mitochondrial
pathway that can directly inhibit the activation of caspase9 and caspase-3.
The death receptor pathway involves the binding of
specific receptor ligands (e.g. TNF-a, FasL) to the tumor
necrosis factor (TNF) receptor, leading to the activation of
caspase-8 and caspase-10 (Boatright and Salvesen, 2003).
These initiator caspases can then activate caspase-3, a
common downstream effector caspase. In addition, caspase-

8 can activate the mitochondrial pathway at an upstream

level by promoting Bax-initiated release of cytochrome c
through cleavage of Bid protein to form tBid (Antonsson
and Martinou, 2000).
The inflammatory pathway involves the formation of the
inflammasome, an analogous complex to the apoptosome. The inflammasome consists of caspase-1, caspase-5,
and an adaptor protein NALP-1 and it is responsible for
converting the inflammatory cytokine pro-IL-1h into its
biologically active form (Martinon et al., 2002). It has
recently been demonstrated that while caspase-1 is not
required for normal developmental apoptosis, it exerts an
important role in hypoxic/ischemic-induced neuronal death.
Upstream, caspase-1 is regulated by Rip2 and downstream it
mediates Bid cleavage to tBid which then facilitates Bax
mediated cytochrome c release (Zhang et al., 2003).
Finally, certain data have emerged that caspase-12, an
inflammatory-like caspase found in the endoplasmic reticulum (ER), may participate as an initiator caspase for ERstress mediated apoptosis (Nakagawa et al., 2000). However, these data remain inconclusive and will require further

L.F Jarskog et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 29 (2005) 846 858

study to establish the exact role of caspase-12 (Lamkanfi et

al., 2004).
2.2. Synaptic apoptosis
Although caspase activation is generally considered a
precursor to rapid cell death, the emerging concept of
synaptic apoptosis suggests that apoptotic activation can be
localized to synapses or distal neurites without inducing
immediate neuronal death (Mattson et al., 1998). Several
studies have found that the apoptotic cascade can be
activated in synaptosomes (preparations that lack nuclear
membranes but are enriched with synaptic elements) by
diverse pro-apoptotic stimuli (Mattson and Duan, 1999;
Gylys et al., 2002). Furthermore, focal application of
glutamate to distal dendrites in vitro can cause a localized
increase in caspase-3 activity in synaptic terminals without
propagation to the neuronal soma (Mattson et al., 1998).
Similarly, h-amyloid applied to distal hippocampal neurites
in compartmented cultures produced localized neurite
degeneration with apoptotic morphology and positive
annexin V binding (a marker for apoptotic activity) without
inducing cell death; pretreatment with the caspase inhibitor
zVAD-fmk blocked these effects (Ivins et al., 1998). Using
in vivo and in vitro models of HIV neurodegeneration,
caspase-3 activity was associated with neurite damage
without initiating an irreversible apoptotic cascade (Garden
et al., 2002). It has been hypothesized that the spread of
localized caspase activity is suppressed by neurotrophic
factors that are also present in neurite terminals (Mattson
and Duan, 1999). Synaptic apoptosis represents a potential
mechanism underlying synaptic remodeling and elimination
in both physiological and pathological conditions and could
also contribute to neuronal plasticity (Gilman and Mattson,
2002; Garden et al., 2002). In Alzheimers disease, this form
of synaptic loss is thought to have direct clinical relevance
by contributing to the early cognitive decline that predates
the onset of large-scale neuronal death (Mattson et al.,
2001).

849

regions did not differ and that the increased density was
secondary to reductions in neuropil (Selemon et al., 1995,
1998). Conversely, other studies have demonstrated
significant layer-specific reductions in the density of
neuronal subpopulations including interneurons in layer
II of prefrontal cortex and in layers II VI of the anterior
cingulate cortex (Benes et al., 1991) and pyramidal
neurons in layer IV of anterior cingulate cortex (Benes
et al., 2001). Furthermore, substantial reductions of
neurons have been identified in several subcortical
regions including nucleus accumbens (Pakkenberg,
1987; Young et al., 2000; Popken et al., 2000; Byne et
al., 2002) but see Cullen et al. (2003) and DorphPetersen et al. (2004). 40% reductions in non-pyramidal
neurons have also been found in CA2 of hippocampus
(Benes et al., 1998). Thus, while large-scale cortical
neuronal loss appears to be absent in schizophrenia, it
appears that discrete reductions in cortical neuronal
populations may occur with laminar and regional
specificity, as well as more substantial reductions in
subcortical neuron numbers.
While certain older studies indicated that schizophrenia
may be associated with cortical gliosis (Stevens, 1982),
most recent studies show an absence of cortical gliosis
(Roberts et al., 1987; Benes et al., 1991; Purohit et al., 1998;
Arnold et al., 1998). Interestingly, a growing number of
studies indicate that schizophrenia may in fact be associated
with reduced glia. These reports include evidence of fewer
oligodendrocytes in prefrontal cortex (Hof et al., 2003),
fewer glial cells in prefrontal cortex (Cotter et al., 2002),
reduced glial fibrillary acidic protein (GFAP)-area fraction
(cell bodies + processes) in prefrontal cortex (Rajkowska et
al., 2002), and fewer glial cells in prefrontal, motor, and
anterior cingulate cortices (Benes et al., 1986; Stark et al.,
2004). Given that glial cells represent a critical source of
neurotrophic support for the surrounding axo-dendritic
arbors and synapses, a reduction in the number of glial
cells may significantly reduce the viability of neurons in
schizophrenia.
3.2. Postmortem studies of neuropil and synaptic markers

3. Neuropathology of schizophrenia
3.1. Postmortem studies of neuronal and glial cell numbers
Reduced numbers of cortical neurons have not
consistently been found in postmortem studies. Using
an unbiased stereological approach, total cortical neuronal
number was unchanged in subjects with schizophrenia
compared to controls (Pakkenberg, 1993). Regionally,
investigators report no evidence of neuronal loss in
prefrontal cortex (Akbarian et al., 1995a; Thune et al.,
2001). Another group found small but significant
increases in neuronal density in prefrontal and occipital
cortex in schizophrenia compared to controls; however,
they concluded that the total number of neurons in these

Several studies have demonstrated increased cortical

neuronal density in schizophrenia (Pakkenberg, 1993;
Selemon et al., 1995; Selemon et al., 1998). The reduced
neuropil hypothesis suggests that increased neuronal
density may reflect a reduction in cortical neuropil (Selemon
and Goldman-Rakic, 1999). Cortical neuropil is primarily
composed of axons, dendrites, and the pre- and postsynaptic
terminals between them. Supporting a potential reduction of
cortical neuropil in schizophrenia is evidence of reduced
dendritic spines and total dendritic length of pyramidal
neurons (Garey et al., 1998; Glantz and Lewis, 2000; Black
et al., 2004), fewer parvalbumin- and GAT-1-immunoreactive varicosities (Pierri et al., 1999; Lewis et al., 2001),
reductions of presynaptic marker proteins including synap-

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L.F Jarskog et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 29 (2005) 846 858

tophysin (Eastwood and Harrison, 1995; Perrone-Bizzozero

et al., 1996; Glantz and Lewis, 1997; Karson et al., 1999)
and SNAP-25 (Thompson et al., 1998; Karson et al., 1999);
but see (Gabriel et al., 1997). Altered synaptic findings also
occur in hippocampus including reduced synaptophysin
(Eastwood and Harrison, 1995; Eastwood et al., 1995;
Vawter et al., 1999), reduced SNAP-25 (Young et al., 1998)
and in temporal cortex in which SNAP-25 is altered
(Thompson et al., 1998). These data are also supported by
an elegant gene array study that identified reduced
expression of multiple genes coding for synaptic gene
products (Mirnics et al., 2000). Taken together, these
findings suggest that synaptic abnormalities are implicated
in the pathophysiology of schizophrenia.
3.3. Neuroimaging studies: evidence of progressive volume
changes
In schizophrenia, cross-sectional magnetic resonance
imaging (MRI) studies have demonstrated evidence of
reduced cortical gray matter volume, both globally (Zipursky et al., 1992; Gur et al., 1998; Hulshoff Pol et al., 2002)
and in cortical subregions including prefrontal (Gur et al.,
1998; Hulshoff Pol et al., 2002), temporal (Schlaepfer et al.,
1994; Gur et al., 1998), and parietal (Schlaepfer et al., 1994)
areas. This data is generally consistent with the postmortem
evidence of reduced cortical neuropil.
However, one of the limitations of cross-sectional studies
is that these do not adequately address whether a change in
brain volume is active or is antecedent to the scan. To
address this issue, investigators have increasingly focused
on longitudinal structural MRI studies. Interestingly, progressive brain volume changes have been identified in
several different patient cohorts including in patients with
prodromal signs of psychosis, childhood-onset schizophrenia, and in new-onset schizophrenia. In a single study of
prodromal patients judged at high risk to transition to
psychosis, a progressive loss of gray matter in certain
hippocampal and frontal regions was found only in those
patients who later developed psychosis (Pantelis et al.,
2003). In childhood-onset schizophrenia, several progressive volume changes have been reported including ventricular enlargement (Rapoport et al., 1997), cortical gray
matter loss in frontal and temporal areas (Jacobsen et al.,
1998; Rapoport et al., 1999) and cerebellar volume loss
(Keller et al., 2003) compared to normal controls. In newonset schizophrenia, progressive ventricular enlargement
has been identified by several groups (DeLisi et al., 1997;
Lieberman et al., 2001; Cahn et al., 2002), but not others
(Gur et al., 1998). Progressive volume loss has been
reported in first-episode schizophrenia in cerebral hemispheres bilaterally (DeLisi et al., 1997), total cerebral gray
matter (Cahn et al., 2002), frontal cortex (Gur et al., 1998),
and in superior temporal gyrus (Kasai et al., 2003), while
Lieberman et al. (2001) did not detect cortical volume
differences.

3.4. Functional neuroimaging and spectroscopy

Reduced metabolic activity in the prefrontal cortex
(hypofrontality) has been demonstrated using positron
emission tomography (PET) and functional MRI (fMRI)
studies in schizophrenia (Weinberger et al., 1986; Andreasen et al., 1997). Studies of phosphorus (31P) magnetic
resonance spectroscopy (MRS) in the prefrontal cortex
found decreased phosphomonoesters (Pettegrew et al.,
1991; Stanley et al., 1995; Hinsberger et al., 1997) and
increased phosphodiesters (Pettegrew et al., 1991; Stanley et
al., 1995) in first-episode schizophrenia. A profile of
reduced phosphomonoesters and increased phosphodiesters
is thought to reflect an accelerated breakdown of membrane
phospholipids (Pettegrew et al., 1993). In addition, several
studies using proton (1H) MRS have reported reduced Nacetylaspartate (NAA) levels in temporal and frontal cortex
in schizophrenia (Bertolino et al., 1998; Cecil et al., 1999).
NAA is generally considered a measure of neuronal
metabolism and reduced NAA levels may therefore reflect
reduced neuronal viability.

4. Apoptosis in schizophrenia
The data reviewed above indicate that the postmortem
neuropathology of schizophrenia is characterized by synaptic and dendritic deficits in cortex and hippocampus,
findings that may be related to neuroimaging evidence of
reduced gray matter volume. Many (but not all) studies have
found reduced neuronal numbers in mediodorsal thalamus
while most cortical regions appear to have no overall
neuronal reductions. Some evidence suggests that layerspecific reductions of neuronal subpopulations occur in
cortex and hippocampus. Increasingly, studies indicate that
cortical glial cell numbers are reduced in schizophrenia.
Given accumulating MRI evidence for progressive volume
changes occurring early in psychosis, the fact that postmortem studies reveal an absence of cortical gliosis, and that
apoptotic mechanisms can produce either cell loss or
synaptic/dendritic loss, the involvement of an apoptotic
mechanism in the pathophysiology of schizophrenia appears
increasingly plausible.
The following sections will review postmortem studies of
apoptosis in schizophrenia, divided into studies of apoptotic
regulatory factors and studies of DNA fragmentation.
Findings will be considered in relation to the hypothesis
that apoptotic mechanisms contribute to the pathophysiology of schizophrenia.
4.1. Apoptotic regulatory proteins
The first study to examine the potential role of apoptosis
in schizophrenia measured levels of the anti-apoptotic
regulatory protein Bcl-2 in postmortem brain tissue (Jarskog
et al., 2000). This study found that Bcl-2 was reduced by

L.F Jarskog et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 29 (2005) 846 858

25% in middle temporal gyrus in schizophrenia compared

to control, Fig 2. Bcl-2 is potently anti-apoptotic, as
demonstrated using in vivo and in vitro systems where
Bcl-2 overexpression was found to protect against proapoptotic stimuli such as ischemia, growth factor withdrawal and glutamate toxicity (Zhong et al., 1993a, b;
Lawrence et al., 1996). Thus, reduced Bcl-2 level may limit
the protection that neurons have against pro-apoptotic
insults, a potentially important deficit in the pathophysiology of schizophrenia. On the other hand, reduced Bcl-2 in
schizophrenia is in contrast to findings in classic neurodegeneration such as Alzheimers disease where cortical
Bcl-2 expression is upregulated and neuronal apoptosis is
accelerated. Higher Bcl-2 levels in classic neurodegeneration are thought to represent a compensatory upregulation in
response to the neurodegenerative process (Satou et al.,
1995), suggesting that the pathophysiology of schizophrenia
is distinct from that of classic neurodegenerative disorders.
However, while low Bcl-2 may signal that apoptosis is not
active in temporal cortex in chronic schizophrenia, it may
alternatively represent a deficit in the ability to mount a
compensatory pro-survival response, as suggested by Benes
et al. (2003). This may significantly increase the vulnerability of neurons and glia to pro-apoptotic stimuli.
Furthermore, as described earlier, Bcl-2 can exert independent neurotrophic properties at the dendrite level as evidenced by enhanced neurite outgrowth and enhanced
neuronal regeneration in Bcl-2 overexpressing neurons.

Bcl-2 U/mg protein

40

30

20

10

Control

Schizophrenia

B
26 kD
1

Fig. 2. (A) Bcl-2 protein levels in middle temporal gyrus (Brodmanns area
21) in healthy control and schizophrenia subjects, measured by enzymelinked immunoassay (ELISA). Bcl-2 was reduced by 25% in schizophrenia
(21.9 T 2.8 Units (U)/mg, mean T S.E., n = 15) as compared to control subjects
(29.3 T 2.1 U/mg, n = 15) by Students t-test (p < 0.05). (B) Representative
Western blot of Bcl-2 protein expression in temporal cortex (30 Ag per lane)
in control (lanes 2,3), schizophrenia (lanes 4,5), bipolar disorder (lanes 6,7)
and major depression (lanes 8,9) subjects with Jurkat lysate in lane 1 as a
positive control for Bcl-2. (Adapted from Jarskog et al., 2000; Reprinted with
permission from the Society of Biological Psychiatry).

851

This suggests that low Bcl-2 levels in temporal cortex in

schizophrenia could contribute to reduced axo-dendritic
branching, independent of the apoptotic mechanism.
To provide another context within which to understand
low Bcl-2 levels in schizophrenia, a follow-up study
measured the ratio of Bax to Bcl-2 in the same temporal
region. The Bax/Bcl-2 ratio is a key determinant regulating
the release of cytochrome c from the mitochondrial membrane and high Bax/Bcl-2 ratios promote cytochrome c
release (Oltvai et al., 1993). Interestingly, the Bax/Bcl-2 ratio
in schizophrenia was increased by 50% compared to control
(Jarskog et al., 2004), Fig 3. A higher mean Bax/Bcl-2 ratio in
schizophrenia is similar to several conditions in which
neuronal apoptosis is known to be accelerated including in
temporal cortex in Down Syndrome (Sawa et al., 1997), in in
vitro cultures modeling h-amyloid toxicity (Paradis et al.,
1996) and in Bax-overexpressing mouse cortex (Oltvai et al.,
1993). Furthermore, given the putative involvement of
glutamatergic mechanisms in the pathophysiology of schizophrenia, it is notable that the ratio of Bax to Bcl-XL (another
anti-apoptotic member of the Bcl-2 gene family) is substantially increased in neonatal rat cortex following brief Nmethyl-d-aspartate (NMDA) receptor antagonism (Wang et
al., 2001). A high Bax/Bcl-2 ratio provides further evidence
that neurons and glia in temporal cortex in schizophrenia are
more susceptible to pro-apoptotic stimuli.
However, in contrast to classic neurodegenerative disorders such as Alzheimers and Parkinsons diseases where
high caspase-3 levels are found in postmortem brain tissue
(Masliah et al., 1998; Hartmann et al., 2000), caspase-3
levels were essentially unchanged and actually trended
toward a slight decrease in schizophrenia temporal cortex
(Jarskog et al., 2004). Since caspase-3 activation is thought
to occur as a final common pathway of apoptosis in the CNS
and serves as a useful marker of such activation (Krajewska
et al., 1997), this provides relatively unambiguous evidence
that apoptosis is, in fact, not active in temporal cortex in
chronic schizophrenia.
Thus, while it appears that the temporal cortex in
schizophrenia may have increased vulnerability to proapoptotic stimuli by virtue of higher Bax/Bcl-2 ratio and an
absolute reduction in Bcl-2 levels, it does not appear that
apoptotic activity whether at cellular or synaptic levels is
increased in this brain region in chronic stages of the
disorder. This, however, does not preclude a role for
apoptosis in earlier stages of the illness. We hypothesize
that apoptotic activity could contribute to the evidence for
progressive neurostructural changes in prodromal and firstepisode psychosis and that the principal substrate affected
by this process is cortical neuropil and that glia and certain
neuronal subpopulations may also be affected, as suggested
by postmortem data reviewed earlier. It is proposed that
caspase-3 and/or other effector caspases could be more
susceptible to activation at the onset of psychosis in
response to a time-limited increase in pro-apoptotic stimuli
(e.g. oxidative stress, glutamate excitotoxicity), especially if

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L.F Jarskog et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 29 (2005) 846 858

Bax/Bcl-2 ratio
(arbitrary units)

2.0

1.5

1.0

0.5

0.0

Control

Schizophrenia

Fig. 3. Bax/Bcl-2 ratio in middle temporal gyrus (Brodmanns area 21) in

healthy control and schizophrenia subjects. Bax and Bcl-2 levels were
determined by semiquantitative Western blot. The mean Bax/Bcl-2 ratio
was 50% higher in schizophrenia (1.65 T 0.23, mean T S.E., n = 15)
compared to control (1.10 T 0.10, n = 15) subjects ( p < 0.05). (Adapted
from Jarskog et al., 2004; reprinted with permission from the American
Journal of Psychiatry, Copyright 2004. American Psychiatric Association).

the Bax/Bcl-2 ratio is already increased at this stage. Then,

after the period of clinical and neurostructural deterioration,
the pro-apoptotic stress attenuates and caspase activity
returns to baseline. Given the paucity of available postmortem brain tissue from patients with first-episode
psychosis, alternative approaches are needed to test this
hypothesis. Possibilities include a longitudinal study measuring apoptotic markers in cerebrospinal fluid in firstepisode psychosis patients as well as using PET imaging for
annexin V (a protein that binds membrane-bound phosphatidylserine which is externalized during apoptosis) in this
same patient group. Increased apoptotic activity in several
neurodegenerative disorders has been suggested by cerebrospinal fluid levels of apoptotic markers (Vermes et al.,
1999; Cid et al., 2003) and by annexin V imaging
(DArceuil et al., 2000; Spence et al., 2003). While the
specific mechanisms by which apoptotic activity could be
activated in schizophrenia are unknown, potential sources of
pro-apoptotic stress in schizophrenia are discussed in the
last section.
Several possibilities exist for integrating apoptotic
mechanisms into the neurodevelopmental hypothesis of
schizophrenia. First, the synaptic pruning hypothesis suggests that abnormalities in normal synaptic pruning and
related neuromaturational processes such as cortical myelination contribute to schizophrenia (Feinberg, 1982; Weinberger, 1987; Keshavan et al., 1994). Reductions in synaptic
density have been demonstrated in human prefrontal cortex
during normal adolescence and early adulthood (Huttenlocher, 1979; Huttenlocher and Dabholkar, 1997), overlapping the age of highest incidence of first-episode
psychosis. While the physiological basis for normal synaptic
pruning is unknown, a potential role for apoptosis is
suggested by evidence that apoptosis can be activated
locally in synapses and terminal dendrites. The possible
roles of apoptosis in the pruning hypothesis of schizophrenia include a contribution to a genetically mediated

acceleration of normal synaptic pruning or to a pathological

potentiation of normal pruning by one or more pro-apoptotic
stimuli.
A second potential overlap between the neurodevelopmental hypothesis of schizophrenia and apoptosis could
occur in very early development. A fetal or perinatal insult
could transiently alter normal developmental apoptosis to
yield enduring cytoarchitectural deficits and altered synaptic
connectivity leading to deficits in brain circuitry. Interestingly, a number of pro-apoptotic stimuli such as ischemia,
hypoxia, and pro-inflammatory cytokines (Thompson,
1995) have been implicated as early life insults that increase
the risk of developing schizophrenia (Geddes and Lawrie,
1995; Gilmore and Jarskog, 1997; Urakubo et al., 2001).
Finally, it should be noted that the evidence for
progressive neurostructural changes in the early stages of
schizophrenia may be due to variables that are not
pathophysiologically related to schizophrenia. It has been
argued that the progressive neurostructural changes in
schizophrenia are probably reversible and represent normal
plastic changes in response to confounding factors such as
the impact of antipsychotic medication, concomitant substance use, poor health and nutrition and lack of environmental stimulation (Weinberger and McClure, 2002).
Further studies are needed to clarify the impact of such
factors on brain structure.
The potential confounding effects of psychotropic
medications and postmortem stability of apoptotic protein
levels have been considered. One week of haloperidol did
not influence Bax, Bcl-2 or caspase-3 levels in rat frontal
cortex (Jarskog et al., 2004); however, another study found
that 1 month of olanzapine and clozapine both increase Bcl2 mRNA and protein by 30 50% in rat frontal cortex (Bai
et al., 2004). Overall, these data suggest that antipsychotic
treatment does not contribute to low Bcl-2 levels in
schizophrenia, although it could be masking even lower
Bcl-2 levels. In another study, 1 month of haloperidol,
quetiapine and clozapine led to 40 50% higher activated
caspase-3 levels in rat frontal cortex (German et al., 2004).
Since caspase-3 levels were not elevated in schizophrenia
cortex, this again does not appear to confound the
postmortem findings other than possibly mask even lower
caspase-3 levels. Finally, high 24-h postmortem stability of
Bax, Bcl-2 and caspase-3 proteins has been determined
(Jarskog and Gilmore, 2000; Jarskog et al., 2004).
Taken together, these data indicate that several apoptotic
regulatory proteins are altered in schizophrenia and that the
vulnerability to apoptotic activation may be increased as
evidenced by high Bax/Bcl-2 ratio and low Bcl-2 levels.
Caspase-3 levels are not increased, indicating a distinct
contrast with the pathophysiology of classic neurodegenerative disorders. The absence of elevated caspase-3 in
postmortem cortex suggests that apoptosis is not active in
chronic schizophrenia. However, we hypothesize that
caspase-3 and other downstream markers of apoptosis may
be upregulated during the period of clinical and neuro-

L.F Jarskog et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 29 (2005) 846 858

structural progression that has been observed around the

new onset of psychosis.
4.2. DNA fragmentation
A common method for visualizing cells undergoing
apoptosis is the TdT-mediated dUTP nick end-labeling
(TUNEL) method. Double-stranded DNA breaks (DSBs)
are associated with irreversible activation of apoptosis and
TUNEL uses in situ hybridization to detect DSBs. TUNELpositive cells in the CNS have been detected in human brain
in settings where large-scale neuronal cell death is known to
be occurring including in early normal development
(Spreafico et al., 1999), in stroke and in Alzheimers
disease (Adamec et al., 1999). However, given that
apoptotic cells are generally cleared rapidly (within 24 h)
and do not leave a residue (Hetts, 1998), TUNEL-positive
cells may be difficult to detect in conditions where cell death
occurs infrequently. Another approach used to study
disorders with lower rates of neuronal death is to measure
single-stranded DNA breaks (SSBs) using the Klenow
technique. SSBs are typically more numerous than DSBs,
are potentially reversible and represent a sensitive indicator
of cells at risk for undergoing apoptosis (Jin et al., 1999).
As reviewed earlier, the anterior cingulate cortex in
schizophrenia represents an area where layer-specific
reductions in neuronal subtypes have been identified (Benes
et al., 1991; Benes et al., 2001). A study using the Klenow
method in anterior cingulate cortex found that, compared to
matched controls, subjects with schizophrenia but not
bipolar disorder had a reduction in a distinct subset of
Klenow-positive neurons that exhibited chromatin clumping
(Benes et al., 2003). This finding suggests that the
regulation of apoptosis is altered in anterior cingulate cortex
in schizophrenia, but that the rate of apoptosis may actually
be reduced rather than increased. In contrast, preliminary
experiments from our laboratory using both the Klenow and
TUNEL methods in temporal cortex do not show altered
rates in the total number of SSBs or DSBs in schizophrenia
or bipolar disorder, suggesting that the rates of DNA
fragmentation may vary by brain region (Glantz et al.,
2003). Given the absence of increased DNA fragmentation,
these data are consistent with the caspase-3 findings
suggesting that cortical apoptosis is not increased in chronic
schizophrenia.
Benes et al. (2003) proposed that their Klenow findings
might either represent a compensatory response to promote
cell survival or, alternatively, a failure of cingulate neurons
to mount an appropriate apoptotic response to an oxidative
challenge. If one posits a baseline increase in pro-apoptotic
stimuli (e.g. oxidative stress) in cortical brain regions in
schizophrenia, then the evidence for low Bcl-2 and low/
normal caspase-3 levels could be consistent with a failure of
apoptotic signaling in response to pro-apoptotic stress.
Alternatively, if pro-apoptotic stress is transiently increased
around the onset of psychosis and largely absent in

853

postmortem tissue (representing patients with chronic

schizophrenia), then low/normal caspase-3 levels would
represent an appropriate compensatory response and that
low Bcl-2 and high Bax/Bcl-2 ratio may reflect a footprint
of earlier pro-apoptotic stress.
4.3. Pro-apoptotic stress in schizophrenia
While many factors have been found to promote
apoptosis, several pro-apoptotic stimuli have also been
suggested to play a role in the pathophysiology of
schizophrenia including glutamatergic excitotoxicity, excess
synaptic calcium flux, oxidative stress, and reduced neurotrophin levels. Data to support the involvement of these
stimuli and pathological processes in schizophrenia and
their potential relationship to apoptosis will be reviewed.
NMDA hypofunction, glutamate excitotoxicity and
altered calcium signaling have all been implicated in the
pathophysiology of schizophrenia (Javitt and Zukin, 1991;
Olney and Farber, 1995; Goff and Coyle, 2001). High
calcium levels, oxidative stress, and mitochondrial dysfunction can all lead to glutamate excitoxicity and each can also
promote apoptotic activity (Mattson and Duan, 1999). Even
very brief NMDA receptor blockade during vulnerable
intervals during rat development can greatly augment
normal developmental neuronal apoptosis (Ikonomidou et
al., 1999). As mentioned earlier, NMDA antagonism can
also produce long-term changes in Bcl-2 gene family
expression including higher pro-apoptotic Bax and lower
anti-apoptotic Bcl-XL as well as increase expression of the
NMDA NR1 receptor subunit (Wang et al., 2001).
Furthermore, altered expression of the NMDA NR1 and
NR2A receptor subunits can increase the apoptotic vulnerability of neurons (Anegawa et al., 2000). Emerging data
implicate changes in these NMDA subunits and others in the
postmortem neuropathology of schizophrenia (MeadorWoodruff and Healy, 2000). Of particular interest, altered
editing of GluR2 mRNA of the AMPA receptor as has been
identified in schizophrenia cortex (Akbarian et al., 1995b)
has been associated with significantly higher calcium flux.
Such flux can lead to neuronal atrophy and apoptosis
(Mattson et al., 1998; Segal et al., 2000). Thus, while the
implications of glutamatergic dysfunction in schizophrenia
remain uncertain, it presents as a candidate mechanism that
can adversely impact neuroapototic processes. In particular,
the susceptibility of cortical neurons to NMDA antagonists
during neurodevelopment suggests a plausible scenario for a
transient activation of apoptosis that could exert limited
neurostructural effects early in the course of schizophrenia.
Oxidative stress is known to cause neuronal apoptosis
and has been hypothesized to contribute to the pathophysiology of schizophrenia (Mahadik et al., 2001).
Serum and red blood cell markers of antioxidant defense
enzymes, including superoxide dismutase, are lower in
patients with first-episode and chronic schizophrenia,
suggesting an inherent vulnerability to oxidative stress

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L.F Jarskog et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 29 (2005) 846 858

(Mukerjee et al., 1996). Other markers of increased

oxidative stress in schizophrenia include increased membrane phospholipid turnover as evidenced by increased
phospholipase A2 activity (Horrobin, 1998) and increased
cortical phosphodiester levels by 31P MRS (Pettegrew et
al., 1993). While the data on oxidative stress may be
more suggestive of a chronic increase in schizophrenia,
many of these are either peripheral markers or relatively
non-specific in vivo neuroimaging markers. It remains
possible that in the CNS, exposure to oxidative stress is
either time-limited or that effective compensatory mechanisms eventually limit the effect of chronic stress,
thereby creating a transient pro-apoptotic environment in
the early stages of schizophrenia.
Neurotrophic factors such as brain-derived neurotrophic
factor (BDNF) and neurotrophin-3 (NT-3) are critical to
neuronal survival and maturation as well as to promoting
synapse formation (McAllister, 2001), and their withdrawals are among the best studied triggers of neuronal
apoptosis (Thompson, 1995). Recent studies have documented reduced levels of BDNF mRNA and protein in
prefrontal cortex in schizophrenia (Hashimoto et al., 2002;
Weickert et al., 2003) as well as concomitant reductions
in the BDNF TrkB mRNA receptor (Hashimoto et al.,
2002). While the basis for lower BDNF levels in
schizophrenia is uncertain, the evidence for fewer cortical
glial cells in schizophrenia may be a contributing factor,
given that glia represent an important source of neurotrophins for CNS neurons. Reduced neurotrophic support
represents another potential source of pro-apoptotic stress
in schizophrenia.

5. Conclusion
Taken together, the neuropathology of schizophrenia
demonstrates reduced neuropil (including dendrites and
synaptic markers) in specific cortical regions and in
hippocampus. There is also evidence of layer-specific
reductions of neuronal subtypes in specific cortical
regions, fewer neurons in the mediodorsal thalamus and
evidence for reduced cortical glial cell numbers. Postmortem data are beginning to implicate apoptotic dysregulation in the pathophysiology of schizophrenia.
Specifically, levels of upstream apoptotic regulatory
proteins appear to increase the vulnerability to apoptotic
stimuli. On the other hand, downstream caspase-3 protein
is not increased, suggesting that excess apoptotic cell
death is not occurring in chronic schizophrenia. Given the
neuroimaging evidence for gray matter loss in the early
stages of psychosis, it is hypothesized that apoptotic
processes such as synaptic apoptosis and regional and
layer-specific neuronal and/or glial apoptosis occur during
this phase of the illness, but that a subsequent compensatory downregulation of apoptosis occurs as illness
moves into a stable chronic stage. Further studies are

needed to test this hypothesis and document that proapoptotic proteins such as caspase-3 are increased in the
CNS during the early phase of the illness. While the
source of pro-apoptotic stress remains uncertain, a
growing body of literature suggests that glutamate
excitotoxicity, oxidative stress, reduced BDNF levels
and increased synaptic calcium flux contribute to the
pathophysiology of schizophrenia, and that these factors,
individually or in concert, can create a pro-apoptotic
environment. The current review has demonstrated that
apoptotic markers are altered in schizophrenia and that
apoptotic mechanisms provide a plausible explanation for
several neuropathological deficits associated with the
disorder.

Acknowledgements
This work was funded by NIMH grants MH-01752
(LFJ), MH-064065 (JAL), NARSAD Young Investigator
Award (LAG).

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