Download A Candidate Molecule Approach to Defining

A Candidate Molecule Approach to Defining
Developmental Pathology in Schizophrenia
by Cynthia Shannon Weickert and Daniel R. Weinberger
across individuals and across cultures (Cutting 1995).
This similarity implies that there may be a common
underlying pathology in the diseased brain. Although this
pathology could have many causes, it is likely that common brain systems or neural circuitry are involved in
most, if not all, cases of schizophrenia. While neither the
neuroanatomical nor the biochemical basis for schizophrenia has been definitively identified, there are provocative leads. Brain imaging studies often demonstrate structural or physiological abnormalities in prefrontal cortex,
cingulate cortex, temporal cortex, or hippocampal formation (Liddle 1995). These findings concur, in general, with
neuropathological studies of the schizophrenic brain that
find evidence of generalized limbic lobe and prefrontal
cortical abnormalities (Falkai and Bogerts 1995). In addition, the fact that the symptoms of schizophrenia are exacerbated by certain pharmacological agents and ameliorated by others has fueled speculation that these brain
abnormalities affect the function of specific neuronal systems, especially those using dopamine, serotonin, glutamate, and gamma-aminobutyric acid (GABA) (Owen and
Simpson 1995).
Neurobiologists attempt to discern the function of the
brain from a highly reductionist perspective; ultimately,
they attempt to understand how the brain functions on cellular and molecular levels. Those working on schizophrenia hope to determine which cells in the brain are affected
by the disease and how the molecules within affected
brain cells are altered. Working at the microscopic level,
neuropathologists throughout this century have searched
the schizophrenic brain for evidence of neuronal dropout.
While some potential clues have been discovered through
this approach, such as evidence of pyramidal neuronal
loss in the entorhinal cortex of schizophrenia patients
Abstract
The evidence that schizophrenia may have its origins
from early in life, possibly during prenatal brain
development, is based primarily on a constellation of
nonspecific anatomical findings and on the results of
surveys of obstetrical complications and of childhood
neurological and psychological adjustment. The developmental processes implicated by this evidence are
uncertain, but speculation has centered around abnormalities of neuronal proliferation, migration, and connection formation. These developmental milestones
are the results of complicated cellular processes involving molecular interactions between cells and between
the extracellular and intracellular milieus. To understand how these abnormalities could relate to schizophrenia, it is necessary to characterize the molecular
events that define the processes. In this article, we discuss the potential impact of a number of molecules
that are important in the sequence of cellular events
implicated in schizophrenia. In particular, we focus on
molecular mechanisms related to cell proliferation,
axonal outgrowth, cell migration, cell survival, synaptic regression, myelination, and developmental aspects
of early adult life. These various candidate molecules
regulate different aspects of cell growth and cell-cell
interactions and are involved in the regulation of
deoxyribonucleic acid (DNA) expression. Very few of
these molecules have been studied in the schizophrenic
brain.
Key words: Puberty, hormone receptors, growth
factors, myelination.
Schizophrenia Bulletin, 24(2):303-316,1998.
Schizophrenia is a brain disease whose cellular and molecular substrates are unknown. Clinically, schizophrenia
can be recognized by a set of symptoms that vary from
subject to subject but still are remarkably stereotyped
Reprint requests should be sent to Dr. D.R. Weinberger, Clinical Brain
Disorders Branch, IRP/NTMH/NIH, NIMH Neuroscience Center at St.
Elizabeths, 2700 Martin Luther King Jr. Ave., SE, Washington, DC
20032.
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C.S. Weickertand D.R. Weinberger
(Jakob and Beckman 1986; Falkai et al. 1988) and evidence of reduced neuronal density in the cortex of
patients with schizophrenia (Benes 1993; Benes et al.
1986), often these findings are not replicable by other
groups (Selemon et al. 1995; Krimer et al. 1997). At the
molecular level, the search has tended to focus on abnormalities in number or affinity of neurotransmitter receptors. Again, while there are reports of abnormal dopaminergic (Seeman et al. 1984, 1993; Murray et al. 1995),
glutamatergic (Deakin et al. 1989; Harrison et al. 1991;
Ishimaru et al. 1994; Breese et al. 1995; Eastwood et al.
19956; Akbarian et al. 1996), and GABAergic receptor
number or distribution (Benes et al. 1992; Akbarian et al.
19956), most of the molecular studies of schizophrenic
brain, thus far have yielded controversial, possibly artifactual, and often nonreproducible findings (Clardy et al.
1994). The reasons for these inconsistencies are probably
many, involving such factors as sample characteristics,
sample size, chronicity, treatment, tissue preparation artifacts, and agonal events. Recognition of the problems
involved in schizophrenia research in postmortem material has led to a reexamination of the methodological
approaches used and an emphasis on hypothesis-driven
searches (Kleinman et al. 1995).
Schizophrenia and Brain Development. One of the
more intriguing recent research directions has been
guided by the increasingly popular notion that schizophrenia is a neurodevelopmental disorder. The neurodevelopmental hypothesis suggests that a brain "lesion" is present
or acquired early in life but does not fully manifest itself
until late adolescence or early adulthood (Weinberger
1987, 1995a). A number of lines of evidence suggest that
the "lesion" does not appear to be progressive in neuropathological terms: no progression of cerebral ventricular size over the course of the illness in most studies
(Jaskiw et al. 1994); no cognitive deterioration over the
course of the illness (Hyde et al. 1994); no evidence of
increased glial membrane turnover signals in magnetic
resonance spectroscopy in either chronic schizophrenia
patients or at the time of disease onset (Bertolino et al.
1996); and no active brain gliosis in most of the postmortem studies (Roberts et al. 1986; Falkai et al. 1988;
Bruton et al. 1990; Benes 1993). Other evidence indicates
that subtle abnormalities of nervous system development
occur early in the lives of patients who manifest schizophrenia later (Jones et al. 1994) and that obstetrical abnormalities are more frequent in such individuals than in
their unaffected relatives (McGrath and Murray 1995).
The neurobiological plausibility of the developmental
hypothesis of schizophrenia has received support from
animal studies showing that a limbic cortical lesion sustained early in life can remain quiescent until after
puberty, when it influences behavioral and neuropharmacological phenomena that mimic schizophrenia to a considerable degree (Lipska and Weinberger 1993, 1996;
Lipska et al. 1993; Flores et al. 1996).
The possibility that schizophrenia is a neurodevelopmental disorder challenges developmental neurobiologists
in two broad areas. First, the molecular nature of the early
lesion in the schizophrenia patient must be identified, and
second, the peripubertal molecular trigger of the phenotypic dysfunction must be denned. As a first step, molecules that are important in normal brain development
must be delineated; with the advent of modern molecular
techniques, hundreds of developmentally important molecules have already been discovered. The purpose of this
review is to discuss, in the broad context of brain development, some of the types of molecules that may play a
role in developmental processes putatively associated
with schizophrenia (see table 1). We believe that in addition to defining structural and functional brain anomalies
and outlining alterations in fast-acting neurotransmitter
systems, it will be important to search for aberrant expression or function of developmentally important molecules
that are capable of interacting with brain elements over
the course of weeks to months to years.
Table 1. Candidate neurodevelopmental
molecules and schizophrenia
Developmental
event
Candidate
molecules
Early pattern
formation
Cell proliferation
HOX family
POU family
FGF family
EGF family
NCAM (Ig family)
Reelin
LAMP
GAP-43
Cell migration
Axonal outgrowth
Survival of
connections
Programmed
cell death
Myelination
Pubertal changes
Findings in
schizophrenia
Fewer NCAM +
neurons
Decreased
GAP-43 mRNA
Decreased
BDNF mRNA
NGF family
NGF receptors
BCL-2 family
p53
Cyclin D
Myelin basic protein
Myelin promoting factors
Estrogen receptor
Androgen receptor
Note.—HOX = homeotic genes; FGF = fibroblast growth factor;
EGF = epidermal growth factor; NCAM = neural cell adhesion
molecule; LAMP = limbic associated membrane protein; GAP =
growth associated protein; NGF = nerve growth factor; NCAM =
neural cell adhesion molecule; GAP = growth associated protein;
mRNA = messenger ribonucleic acid; BDNF = brain-derived neurotrophic factor.
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induction and specification of cell position within the
neural tube (Purves and Lichtmen 1985). Signals originating from the notochord are believed to convey dorsal-ventral positioning information to the cells in the developing
neural tube. Initial rostro-caudal cell positioning is related
to activation of distinct genes that regulate the orientation
of parallel segments of the anterior-posterior body axis.
These genes encode transcription factors that share a
deoxyribonucleic acid (DNA) binding motif (the "homeobox"), allowing them to act as master switches to direct the
morphogenic development of each segment of the embryo
(McGinnis et al. 1984; Scott and Weiner 1984; Gehring
1987; Ingham 1988). Protein products of homeobox genes,
including, for example, homeotic genes (HOX) family
members, return to the cell nucleus and bind to certain
DNA sequences, enabling the activation or inactivation of
other genes in spatially restricted domains of the embryo
(Holland and Hogan 1988; Goulding and Gruss 1989;
Wilkinson et al. 1989; Lufkin et al. 1991). If one of these
early acting gene products were altered in schizophrenia,
one might expect to find much greater alterations in gross
brain morphology than the subtle ones found in the schizophrenic brain. Indeed, a recent report has confirmed that a
mutation in a homeobox gene is associated with marked
schizencephaly, a gross defect in telencephalic fusion
(Brunelli et al. 1996). However, other families of homeobox-like transcription factors can operate later in development or appear only in defined brain regions. An example
of these more specific transcription factors can be found
among the so-called POU family of genes (Ingraham et al.
1988; Treacy and Rosenfeld 1992). For example, SCIP, a
homeodomain protein member of the POU III family, is
expressed specifically in layer V neurons of the adult cortex
and only begins expression in this population of neural
cells after they have started to differentiate (Frantz et al.
1994). Other POU HI family members have been shown to
be activated at various times before and after birth in discrete regions of the brain (Le Moine and Young 1992;
Mathis et al. 1992). Therefore, transcription family molecules that fit this developmental temporal pattern are more
likely to be candidate molecules in schizophrenia.
Molecular Brain Development Broadly Defined.
Development of a multicellular organism requires that
each genetically identical cell of the body, which is
derived initially from one individual cell, take on a dissimilar or differentiated phenotype. Initially, brain development is driven by a genetic program that activates a molecular cascade of events leading to the turning on and
turning off of particular genes in cells (Purves and
Lichtmen 1985; Gilbert 1991; Jacobson 1991; Ptashne
1992). It is critical that the correct spatial and temporal
profile of gene expression be maintained for cells to differentiate down specific lineages, such as neuron versus
astrocyte, and thus for the brain to develop normally (Raff
et al. 1983; Cooke 1988; Patel 1994; Rubenstein et al.
1994). As an organism grows, specification of cell fate
relies increasingly on molecular signals extrinsic to the
developing cell. Such signals can be derived from cell surface molecules on neighboring cells or diffusible chemicals emanating from both nearby and distant cells.
Coordinated brain development results from activation and
inactivation of genes in certain cells and not others, and
this process produces a spatially and temporally unique
pattern of proteins that, in turn, determines which cells are
capable of sending or receiving messages from other cells.
Genes, Neurodevelopment, and Schizophrenia. A
large number of genetic studies have indicated that inheriting certain genes imparts risk for developing schizophrenia (Asherson et al. 1995). If a faulty gene has been inherited by an individual not yet exhibiting symptoms of
schizophrenia, it may affect brain development and susceptibility to schizophrenia in two general ways. First,
one may speculate that this gene normally transcribes proteins that are important for normal brain development or,
alternatively, that the "wild-type" allele of this gene
becomes activated only at the time of early adulthood
when the protein product becomes necessary. Second,
defective genes may impart susceptibility to the illness by
sensitizing the organism to environmental adversity. It has
been postulated that the "lesion" results from an abnormal
prenatal, natal, or early postnatal environment that
adversely affects the developing brain and alters the normal course of developmental events (Weinberger 19956).
A genetic deficit could conceivably predispose an individual to this adversity or modify its effects. By either mechanism, it is apparent that the brain "lesion" in schizophrenia could be caused by genetic factors, environmental
factors, or more likely some combination of both.
Cell Proliferation. Another very early event in brain
development is the exponential increase of cell number
inside the neural tube (Jacobson 1991). Some reports have
shown a reduced number of neurons in the adult schizophrenic brain (Hopf 1952; Vogt and Vogt 1952; Colon
1972; Benes et al. 1986). One possible explanation is that
fewer neurons were produced at the outset, either because
of reduced proliferation or because fewer neurons in the
diseased brain differentiated. Protein molecules have been
shown to regulate these events by stimulating receptors on
the cell surface of dividing cells. These extracellular sig-
Candidate Molecules
Early Pattern Formation. Some of the first tasks
accomplished by the developing organism are neural tube
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C.S. Weickert and D.R. Weinberger
away from the zone of origin to an appropriate brain layer
in the maturing brain (Jacobson 1991). Recent evidence
has suggested that there are an abnormally high number of
neurons in white matter areas of schizophrenic brain
(Akbarian et al. 1993&, 1996). One possibility is that these
displaced neurons may not have successfully migrated to
their appropriate cortical layer during development. Such
aborted migration could be the result of inappropriate
migratory cues along the migratory route or an inability of
the neurons to respond to those cues. At a molecular level,
cell migration is thought to result from the combinatorial
adhesive or repulsive action of many cell surface proteins
and glycoproteins present on the neuron and along the
migratory route (commonly, radial glia). Three main families of adhesion molecules can be located on the cell surface: the immunoglobulin superfamily, the cadherins, and
the integrins (Jessell 1991). Cell adhesion proteins exist in
more than one form, and these forms may be related to
specific developmental or functional abilities. For example,
the neural cell adhesion molecule (NCAM), a member of
the immunoglobulin superfamily, has a heavily polysialated (PSA) form that has been shown to be involved in
promoting the migration of immature neurons out of the
adult neurogenic subependymal layer (Ono et al. 1994).
The PSA residue makes the NCAM molecule less sticky so
it facilitates neuronal movement (Acheson et al. 1991; Ono
et al. 1994). One study suggests that there may be a lower
number of neurons expressing the polysialic form of the
NCAM molecule in the schizophrenic hippocampus
(Barbeau et al. 1995). The abnormal levels of PSA-NCAM
in the schizophrenic brain might lead to migration abnormalities, resulting in inwardly displaced neurons.
Extracellular matrix molecules and glial cell adhesion
molecules should also be considered components of
molecular migration machinery (Gao et al. 1992). When
an extracellular matrix protein molecule is altered during
brain development, a dramatic phenotype can result. In
the mutant mouse reeler, for example, later-born cortical
neurons are unable to migrate past the earlier-born cortical neurons, resulting in an atypical "inside-out" pattern
of cortical lamination (Caviness and Rakic 1978). This
reorganization of cortical lamination was recently found
to be the result of a mutation in a single gene, the reelin
gene, which codes for a secreted protein localized to the
extracellular matrix (D'Arcangelo et al. 1995). Little is
known about extracellular matrix molecules in schizophrenia. Clearly, more postmortem studies on brains from
schizophrenia patients are needed to examine this interesting and diverse group of molecules that promote neuronal
cell adhesion.
nals include classes of molecules, termed growth factors
or cytokines, that stimulate the proliferation and differentiation of brain cell precursors (Gospodarowicz 1983).
Among these are members of the fibroblast growth factor
(FGF) family (Bouvier and Mytilineou 1995) and the epidermal growth factor (EGF) family (Reynolds and Weiss
1992; Reynolds et al. 1992). Many growth factors can
exist in both membrane/substrate bound and secreted
forms, and accordingly they are thought to exert contactdependent and diffusible effects (Carpenter and Cohen
1990). Most growth factors bind to cell surface receptors
and activate tyrosine kinase second messenger systems to
transduce mitogenic signals (Pawson and Bernstein
1990). It is conceivable that a decreased level or an
altered form of growth factor or growth factor receptor
limits the production of neuronal cells early in the brain
development of a schizophrenia patient.
A surprising result highlighted by recent basic
research demonstrates that the proliferation of neurons
continues in the adult avian and rodent brain in a specialized area called the subependymal zone (Altman 1969;
Alvarez-Buylla et al. 1990). This putative neurogenic
zone lies just under the ependymal cell layer surrounding
the lateral ventricle in the adult. Members of the EGF
family of growth factors have been shown to stimulate the
proliferation of these adult stem cells in the brains of
rodents (Weickert and Blum 1995; Craig et al. 1996).
Thus, some of the factors that may be involved in stimulating fetal brain cells to divide may still be inducing proliferation of stem cells in the adult brain. Recent evidence
gathered from cultures of human temporal lobe biopsies
suggests that neuronal production may also continue in
the adult human brain (Kirschenbaum et al. 1994).
By examining the putative mitogenic subependymal
layer in adult human neuropathological specimens,
researchers may be able to define the factors shared by
adult and fetal neurogenesis. This zone may provide
researchers with a window for exploring molecules that
have operated during development of the fetal brain.
Currently, nothing is known about which growth factor
molecules or receptors continue to be expressed in the
adult human putative neurogenic zones. If neurogenesis
occurs in adult human brains, then either a reduction in
neuron number without gliosis or a neuronal overabundance could reflect abnormalities in postnatal neuronal
proliferation. As our knowledge about brain development
expands, our ideas of the potential mechanism for the
developmental "lesion" in schizophrenia will likely
evolve along with it.
Cell Migration. In both the adult brain and the developing brain, after a cell exits the cell cycle and has become
committed to the neuronal phenotype, it must migrate
Axonal Outgrowth. Once a cell body of a neuron has
migrated to the appropriate cortical location, axonal con-
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Developmental Pathology in Schizophrenia
nections made by these neurons are less plastic. A recent
study that employed 3IP nuclear magnetic resonance
found a decrease in the growth of membranes and an
increase in the breakdown of membranes in the prefrontal
cortex of first-episode schizophrenia patients compared
with healthy controls (Pettegrew et al. 1991). These findings, along with our own, suggest that there may be a
reduction in growth-associated activities in the schizophrenic prefrontal cortex and that molecules implicated in
axonal growth and synaptic plasticity should be investigated further in the schizophrenic brain.
nections with other neurons are established. The swollen
tip of a growing axon, the growth cone, is thought to integrate extracellular signals in order to ensure proper phosphorylation and dephosphorylation of cytoskeletal elements, which in turn propel the growing tip of the axon in
an anatomically correct direction (Kater and Guthrie
1990). Neuroscientists have hypothesized that either
fewer cortico-cortical connections or dysfunctional ones
may underlie the deficits in higher level cognitive tasks
that are manifested by most patients with schizophrenia
(Weinberger and Lipska 1995). The diminution of cortical
neuropil and the reduction in synapse marker proteins in
the cortex support the idea that there are fewer cortical
connections in the diseased brain (Browning et al. 1993;
Eastwood and Harrison 1995; Eastwood et al. 1995a;
Selemon et al. 1995).
One may speculate that fewer cortico-cortical connections are initially established in the developing schizophrenic brain. Many different proteins are involved in the
complex process of axon elongation; these molecules
range from cell adhesion molecules and neurotransmitter
receptors to microtubules and neurofilaments (Kater and
Guthrie 1990; Reichardt et al. 1990). One example of a
cell adhesion molecule critical to axon elongation is limbic associated membrane protein (LAMP). LAMP is
highly expressed by cortical and subcortical neurons comprising the limbic system and has been shown to promote
selective neurite outgrowth from limbic cortical neurons
(Levitt 1984; Pimenta et al. 1995; Zhukareva and Levitt
1995). Abnormal expression of LAMP could underlie the
functional and pathological alterations in limbic system
connectivity implicated in the schizophrenic brain; therefore, LAMP would be well worth investigating in postmortem specimens.
Another molecule integral to normal axonal outgrowth and targeting of a more general nature is growth
associated protein 43 (GAP-43). GAP-43, an internal
phosphoprotein essential to growth cone migration, is
localized subcellularly to the inner leaflet of the presynaptic membrane (Skene 1989; Shea et al. 1991). GAP-43,
messenger ribonucleic acid (mRNA), and protein have
been found to be abundantly expressed in neurons that
reside in areas of the adult human brain that are thought to
be highly plastic, such as the limbic and prefrontal cortices (Neve et al. 1987, 1988; Benowitz et al. 1989). This
finding implies that GAP-43 not only functions during
developmental axon outgrowth, but also may have an
important role in the modulation of neuronal connections
later in life. In ongoing studies, we have found that the
levels of GAP-43 mRNA are reduced in the adult schizophrenic prefrontal cortex (Geethabali et al. 1996). This
may suggest that there are fewer connections emanating
from the schizophrenic prefrontal cortex, or that the con-
Survival of Neuronal Connections.
The ability to
maintain connections with other neurons or postsynaptic
sites is necessary for long-term neuron survival (Purves
and Lichtmen 1985). During brain development, neurons
initially send out an exuberance of connections, and
waves of these connections, especially the excitatory
ones, are eventually pruned (Cowan et al. 1984). Pruning
of connections can result from a reduction of axon collaterals or from the actual death of neurons. Thought of in
another way, pruning may reflect the failure of competitive survival of connections. Neurons compete for limited
amounts of target-derived growth factors, which are taken
up by axon terminals and transported back to the nerve
cell body to promote neuron survival (Levi-Montalcini
and Booker 1960; Levi-Montalcini and Angeletti 1968;
Levi-Montalcini 1987). Reports show decreased cortical
volume, smaller neuron size, and reduced neuropil in the
schizophrenic brain (Falkai and Bogerts 1995; Selemon et
al. 1995). Thus, neurons found in a schizophrenic brain
may be less viable than those harbored in a healthy brain,
and this decreased viability could result from alterations
in the availability of growth factors.
Neuronal growth factors consist of many different
families of growth factor peptides, some of which may
overlap with the mitogenic growth factors previously
described (Casper 1996). The neurotrophin growth factor
(NGF) family is the best example of peptides that induce
process outgrowth, increase soma size, and support the
survival of central nervous system neurons (Glass and
Yancopoulos 1993). Some examples of the NGF family
that have been shown to support the survival and process
outgrowth of dopaminergic, serotonergic, glutamatergic,
and GABAergic neurons are brain-derived neurotrophic
factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin4/5 (NT4/5) (Glass and Yancopoulos 1993). hi preliminary
studies, investigators in our laboratory have found a reduction in BDNF mRNA in the hippocampus of schizophrenia
patients compared with controls, suggesting that there may
be less trophic support available to hippocampal afferents
in the schizophrenic brain (Brouha et al. 1996). The finding of less capability of neurotrophic factor synthesis in
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C.S. Weickert and D.R. Weinberger
the postmortem schizophrenic brain lends molecular support for the suggestion that a functional disconnection of
cortical areas occurs in the schizophrenic cortex
(Weinberger and Lipska 1995). The neurotrophins, as well
as their receptors and other related growth factor molecules, merit further investigation in schizophrenia patients.
Programmed Cell Death. A reduction in trophic support to a neuron is thought to result not only in synaptic
pruning, but also in the initiation of so-called programmed cell death of the neuron, a complex involutional
cellular process involving a sequence of cellular and
genetic steps and ultimately leading to DNA fragmentation (Steller 1995). In the developing nervous system,
about 50 percent of the neurons originally generated
undergo programmed cell death (Oppenheim 1991).
Programmed cell death, or apoptosis, is often contrasted
with necrosis, which refers to death of a cell by some
injury or insult, as in mechanical damage, infarction, and
infection (Fawthrop et al. 1991). Necrosis is accompanied
by an inflammatory response, whereas programmed cell
death is not believed to trigger inflammation. The exact
distinction between these two types of cell death is still
being debated, however, and probably will involve some
overlap (Server and Mobley 1991). Most of the studies
that show a reduction of numbers of neurons in the schizophrenic brain do not report an increase in numbers or
reactivity of glial cells (Falkai and Bogerts 1995). The
absence of gliosis may be a signal that the "damage," or
putative loss of neurons, in the schizophrenic brain has
occurred much earlier and therefore the astrocytic
response either did not occur or was resolved long before
the tissue was examined. Alternatively, fewer neurons in
the schizophrenic brain could be the result of an increase
in programmed cell death.
In addition to extracellular trophic molecules that are
thought to be able to prevent this programmed cell death,
many intrinsic factors, such as molecules that act primarily inside the cell, are involved in executing the cell death '
response itself. One factor is the peptide BCL-2, first discovered in B-cell lymphomas (Tsujimoto et al. 1984).
Overexpression of the BCL-2 protein, normally located in
the inner membrane of mitochondria, allows neural cells
to survive the withdrawal of growth factors, an event that
otherwise leads to cell death (Zhong et al. 1993). BCL-2
is the prototypical member of a family of related cytoplasmic proteins whose members can induce or prevent programmed cell death, including BCL-X, BAX, and BAD
(Davies 1995). A variety of protein factors that reside in
the nucleus have also been shown to be key regulators of
programmed cell death. One of these nuclear factors, p53,
can mediate DNA repair, and another, cyclin D, is involved in cell cycle regulation (Freeman et al. 1994;
308
Wood and Youle 1995). Some of the factors thought to be
involved in cancer can also be key regulators of programmed cell death (Fischer et al. 1986). Interestingly,
there have been several reports of a resistance to cancer in
schizophrenia patients despite frequent nicotine abuse
(Gopalaswamy and Morgan 1986; Harris 1988;
Mortensen 1994). Little is known about the expression or
regulation of cell death factors in the normal or schizophrenic central nervous system. Programmed cell death
regulators and effectors may be important molecules to
add to the list of candidate molecules for further study in
the schizophrenic brain.
Cortical Subplate. A transient layer of cortical neurons,
termed the subplate, lies underneath the developing cortical
mantle, below the future cortical layer (Shatz et al. 1990).
The early maturing subplate neurons form the first connections between cortical-subcortical and cortical-cortical
areas and are believed to provide a scaffold required for the
proper formation of adult cortical afferents and efferents
(Shatz et al. 1990). Approximately 80 to 90 percent of subplate neurons undergo cell death during development, and
thus very few subplate neurons are normally found in the
adult brain (Kostovic and Rakic 1990; Shatz et al. 1990).
The cellular and molecular mechanisms responsible for the
developmental reduction in numbers of subplate neurons
are not known, but neurotrophic factors and apoptotic factors are likely to be involved. The finding of increased neurons in the cortical white matter of some schizophrenia
patients, described previously, has been interpreted as an
overrepresentation, or increased survival, of these early
subplate neurons (Akbarian et al. 1993a, 19936, 1995a). It
may be that subplate neurons in the schizophrenic brain
make anomalous and sustainable connections that prevent
their programmed cell death and their normal disappearance during development. Alternatively, the subplate neurons in the schizophrenia patient may have abnormal apoptotic molecular machinery normally required for executing
the programmed cell death response and therefore the subplate neurons survive. In the schizophrenic brain, subplate
neurons may survive longer because they encounter less
competition for target-derived trophic support. If this were
the case, then the displaced subplate neurons would not be
the site of primary pathology, but would merely reflect an
absence of neurons elsewhere and thus a loss of competing
efferents. Studies of molecules that regulate survival and
death of human cortical subplate neurons in the schizophrenic brain seem advisable.
Myelination. Central nervous system neurons that make
long-distance connections may have their axons
ensheathed in the insulating substance myelin, produced
by oligodendroglia during many stages of brain develop-
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Developmental Pathology in Schizophrenia
ment. In general, the majority of oligodendroglia and
astrocytes are believed to be generated after the wave of
neurogenesis in most brain regions, although there can be
considerable temporal overlap (Smart 1961; Smart and
Leblond 1961; Sturrock and Smart 1980; Cameron and
Rakic 1991). Myelination of tracts in the human brain
begins during fetal life in some areas and in early postnatal life in others (Yakovlev and Lecours 1967).
Myelination can continue well into the second and third
decades of life, especially for cortico-cortical relays
(Yakovlev and Lecours 1967; Benes 1989; Benes et al.
1994). A variety of factors have been shown to induce or
suppress production of myelin basic protein, a major component of myelin often used as an index of myelin production itself. These myelin-modifying factors include ciliary neurotrophic factor (CNTF), basic fibroblast growth
factor (bFGF), insulin-like growth factor (IGF), and
platelet-derived growth factor (PDGF) (Cameron and
Rakic 1991; Collarini et al. 1991; Goldman 1992). If there
is functional disconnection of cortical regions in schizophrenia, the underlying cause may be that the nerveimpulse insulating myelin is somehow disrupted. This
theoretical possibility is supported by evidence that schizophrenialike psychoses are a frequent manifestation of the
dysmyelination disorder metachromatic leukodystrophy
(Hyde et al. 1992). However, there is no evidence yet of
abnormal myelin or myelination in the schizophrenic
brain. To explore the hypothesis that the molecular
aspects of myelination may be abnormal in the schizophrenic brain, myelin could be examined for abnormal
molecular composition or structure, and if myelin is found
to be aberrant, then factors regulating myelin metabolism
could be examined.
(Feinberg 1982). However, in the widely cited study
examining the density of synaptic profiles in the postnatal
human prefrontal cortex, few teenage human brains were
actually examined (Huttenlocher 1979). In fact, adolescence (i.e., between the ages of 12 and 20) is a time of
considerable brain growth in certain areas of the human
cortex. Indeed, peripubertal changes occurring in the
human brain represent a combination of regressive and
progressive events (Thatcher et al. 1987; Jernigan et al.
1991; Buchsbaum et al. 1992).
Many parameters of synaptic communication change
across distinct cortical regions concurrently in adolescence; a change in hormonal status may orchestrate these
changes (Lidow and Rakic 1992). Puberty in humans is
recognized somatically by a spurt in the growth of the
bones and the head, extension of new hair follicles, and
attainment of sex organ maturity (Epstein 1986).
Psychological theorists have outlined specific cognitive
changes that occur at the time of puberty (Kaplan and
Sadock 1988). Little is known about the cellular or molecular substrates underlying these brain changes, but it
would not be unreasonable to suspect that changes in the
steroid hormone milieu during puberty underlie or drive
the changes in neuronal populations that subserve mood,
cognition, and sociality (Ojeda 1991). A recent positron
emission tomography study from our group (Berman et al.
1997) has shown that sex steroids can modulate prefrontal
cortical physiology during the Wisconsin Card Sorting
Test (WCST; Heaton 1981), but the molecular substrate of
this effect is unknown. A question for researchers working
on schizophrenia is: How do the hormonal changes surrounding puberty influence the maturation or function of
"higher level" cortical association areas?
The effects of steroids can be mediated directly on
neurons by lipophilic diffusion of the steroid into the cell
and by high affinity binding to cytoplasmic receptors.
Upon binding of hormones, the steroid hormone receptor
complex translocates to the nucleus and binds to hormone
response elements in DNA to activate or repress gene
transcription (Evans 1988; Glass 1994; Williams 1994).
Steroid hormones can coordinate brain maturation
through their action as transcription factors. Surprisingly,
evidence of changes in estrogen and androgen receptors in
the human brain during postnatal development is scarce
(Tohgi et al. 1995), although work in the primate does
show that androgen and estrogen receptors are distributed
throughout many cortical regions during postnatal development (MacLusky et al. 1987; Clark et al. 1988).
Anatomical localization of steroid hormone receptors in
the human brain would be a first step toward understanding how peripubertal changes in circulating sex steroids
could influence the maturation and function of brain systems possibly involved in schizophrenia.
Molecular Aspects of Emergent Psychosis. Most of
the major developmental brain events considered previously are thought to have taken place before the onset of
adolescence, although we consider certain "developmental" events as ongoing processes. One of the most characteristic clinical aspects of schizophrenia is its onset in
early adulthood. The reason for this is unknown. One
could speculate that the maturational events that normally
occur in late adolescence or early adulthood do not proceed successfully in the schizophrenic brain. Numerous
neurobiological substrates of peripubertal brain changes
include changes in dopaminergic, serotonergic, adrenergic, glutamatergic, GABAergic, and cholinergic neurotransmitter systems (Brooksbank et al. 1981, 1982;
Goldman-Rakic and Brown 1982; Rakic et al. 1986;
Lidow et al. 1991; Lidow and Rakic 1992; Court et al.
1993). It has been suggested that adolescence may be a
time of marked synaptic pruning in normal development
and that synaptic pruning is altered in schizophrenia
309
Schizophrenia Bulletin, Vol. 24, No. 2, 1998
C.S. Weickert and D.R. Weinberger
Non-sex hormones also play a role in the maturational changes in the brain at or around the time of
puberty. For example, thyroid hormone is critical for
proper cortical maturation before puberty, and thyroid
hormone can regulate cortical synaptogenesis (Dussault
and Ruel 1987; Stein et al. 1989). Although thyroid hormone levels are reported to be in the normal range in
schizophrenia patients, little is known about thyroid hormone receptors and downstream effectors of thyroid hormone action in the diseased brain. Another point worth
noting is that steroids do not exert their effects in isolation; their transcriptional ability is often regulated by
complex protein-protein interactions with other transcription factors (Lazar 1993; Glass 1994; Forman et al. 1995),
including interactions between hormone receptor molecules such as thyroid hormone receptors, glucocorticoid
receptors, and retinoic acid receptors. While an understanding of these interactions in the developing brain is
still in its very early stages, schizophrenia researchers
should not dismiss the steroid/thyroid hormone superfamily members as potential molecules involved in schizophrenia (Goodman 1995).
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114(1): 143-153,1991.
Akbarian, S.; Bunney, WE., Jr.; Potkin, S.G.; Wigal, S.B.;
Hagman, J.O.; Sandman, C.A.; and Jones, E.G. Altered
distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase cells in frontal lobe of schizophrenics
implies disturbances of cortical development. Archives of
General Psychiatry, 50:169-177, 1993a.
Akbarian, S.; Huntsman, M.M.; Kim, J.J.; Tafazzoli, A.;
Potkin, S.G.; Bunney, W.E., Jr.; and Jones, E.G. GABAA
receptor subunit gene expression in human prefrontal cortex: Comparison of schizophrenics and controls. Cerebral
Cortex, 5(6):550-560, 1995a.
Akbarian, S.; Kim, J.J.; Potkin, S.G.; Hagman, J.O.;
Tafazzoli, A.; Bunney, W.E., Jr.; and Jones, E.G. Gene
expression for glutamic acid decarboxylase is reduced
without loss of neurons in prefrontal cortex of schizophrenics. Archives of General Psychiatry, 52:258-266,
1995ft.
Akbarian, S,; Kim, J.; Potkin, S.G.; Hetrick, W.P.;
Bunney, W.E., Jr.; and Jones, E.G. Maldistribution of
interstitial neurons in prefrontal white matter of the brains
of schizophrenic patients. Archives of General Psychiatry,
53:425^36, 1996.
Conclusion
Akbarian, S.; Vinuela, A.; Kim, J.J.; Potkin, S.G.; Bunney,
WE., Jr.; and Jones, E.G. Distorted distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase neurons in temporal lobe of schizophrenics implies anomalous cortical development. Archives of General
Psychiatry, 50:178-187,1993ft.
While maturational changes occurring in the schizophrenic brain in early adulthood may be simply unmasking the prior "lesion," identifying which neurons undergo
molecular changes around the time of puberty may help
us to decipher which neurons have suffered a developmental "hit." Delineating these molecular changes may
give us insight into the molecular events involved in the
activation of molecular systems that fail in schizophrenia
because they depend on and interact with potentially
abnormal genes or proteins. Many developmentally
important molecules continue to be expressed in the adult
brain, and their in vivo function is rarely firmly established; they may play a role in synaptic rearrangements
thought to underlie brain plasticity and learning. Most
autopsy specimens are from adult brains, and while adult
expression of developmentally important molecules facilitates the study of these molecules, investigators may be
left questioning the developmental significance of their
findings. Ideally, it is desirable to undertake studies of
normal human brain development to help determine the
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The Authors
Cynthia Shannon Weickert, Ph.D., is IRTA Fellow, and
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