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Neurodevelopment, neuroplasticity, and new genes for schizophrenia.

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Progress in Brain Research, Vol. 147
ISSN 0079-6123
Copyright ß 2005 Elsevier BV. All rights reserved

CHAPTER 23

Neurodevelopment, neuroplasticity, and new genes

for schizophrenia

Steven E. Arnold*, Konrad Talbot and Chang-Gyu Hahn

Cellular and Molecular Neuropathology Program, Center for Neurobiology and Behavior, Department of Psychiatry,
University of Pennsylvania, Philadelphia, PA 19104, USA

Abstract: Schizophrenia is a complex, debilitating neuropsychiatric disorder. Epidemiological, clinical, neuropsycho-

logical, and neurophysiological studies have provided substantial evidence that abnormalities in brain development and
ongoing neuroplasticity play important roles in the pathogenesis of the disorder. Complementing these clinical studies,
a range of cytoarchitectural, morphometric, ultrastructural, immunochemical, and gene expression methods have been
applied in investigations of postmortem brain tissues to characterize the cellular and molecular profile of putative
developmental and plastic abnormalities in schizophrenia. While findings have been diverse and many are in need of
replication, investigations focusing on higher cortical and limbic brain regions are increasingly demonstrating
abnormalities in the structural and molecular integrity of the synaptic complex as well as glutamate-related receptors
and signal transduction pathways that play critical roles in brain development, synaptogenesis, and synaptic plasticity.
Most exciting have been recent associations of schizophrenia with specific genes, such as neuregulin-1, dysbindin-1, and
AKT-1, which are vital to synaptic development, neurotransmission, and plasticity.

Introduction schizophrenia commit suicide (Hafner and Heiden,

Schizophrenia is a severe, chronic mental illness
with a lifetime prevalence of 0.12–1.6% worldwide
(Goldner et al., 2002). Diagnosis is typically
established in late adolescence or early adulthood,
when the disease’s characteristic psychiatric features
become evident and it often leads to a lifetime of
suffering for both patient and family. In a recent
World Health Organization report on the burden of
disease in developed countries, schizophrenia ranked
fifth among all illnesses in the number of years lost to
disability (Murray and Lopez, 1996). It is associated
with significant mortality as 4–14% of people with
*Corresponding author. Tel.: +1-215-573-2840;
Fax: +1-215-573-6382; E-mail: sarnold@med.upenn.edu
2003).
Schizophrenia is best recognized by the presence of
the so-called ‘‘positive’’ symptoms of schizophrenia
(Eaton et al., 1995; Hafner and Heiden, 2003), which
include hallucinations, delusions, and thought dis-
order. Less conspicuous, though more disabling are
the ‘‘negative’’ and cognitive symptoms of schizo-
phrenia (Eaton et al., 1995; Hafner and Heiden, 2003),
which include apathy, social withdrawal, flatness of
emotion and affect, and anhedonia that constitute the
real deterioration in personality that occurs with the
disease. Further, as discussed in greater detail below,
there has been increasing recognition of significant
cognitive deficits in persons with schizophrenia,
especially in attention, memory, and executive
functions (Gur et al., 2000; Goldberg et al., 2003)
that also contribute greatly to disability. Treatment

DOI: 10.1016/S0079-6123(04)47023-X 319

320
with dopamine-antagonist medications can be very
effective in eliminating or diminishing the positive
symptoms of schizophrenia, but to date, medications
have shown little ‘‘if any’’ benefit for the negative and
cognitive symptoms (Miyamoto et al., 2003).
The pathogenesis of schizophrenia as a brain
disorder has been a matter of intense scrutiny for
over a century. Emil Kraepelin’s initial formulation
of schizophrenia as ‘‘dementia praecox’’ highlighted
deteriorative aspects of the disease and raised the
possibility of neurodegeneration as the cause
(Kraepelin, 1919). Supporting that notion is the
clear behavioral, cognitive and functional deteriora-
tion with disease onset, which in some patients
continue and culminate in a state resembling
neurodegenerative dementias in late life. However,
almost without exception, postmortem studies have
failed to find any increase in gliosis, apoptosis,
neurodegenerative disease lesions (e.g., amyloid
plaques, neurofibrillary tangles, Lewy bodies, or
other filamentous inclusions), or other indicators of
neuronal death or injury (e.g., ubiquitination), even
in elderly, severely regressed persons with schizo-
phrenia (Arnold et al., 1998; Harrison, 1999).
On the other hand, presence of neurodevelop-
mental anomalies in schizophrenia has long been
recognized. Hecker, Kraepelin, and Bleuler all
commented on premorbid physical, mental, and
behavioral abnormalities (Hecker, 1871; Kraepelin,
1919; Bleuler, 1924; Marenco and Weinberger, 2000).
Contemporary clinical and neurobiological evidence
increasingly support the role of abnormal neuro-
development in the pathogenesis of schizophrenia
(Arnold and Rioux, 2001; Weinberger and Marenco,
2003). Data from neuropsychological, functional
neuroimaging, electrophysiological, genetic, and
molecular neuropathological studies also suggest
abnormalities in neuroplasticity, impairing the
adaptive capacity of multiple neural systems to
respond to environmental stimuli and experience in
schizophrenia. The effects of normal maturation and
aging processes interacting with schizophrenia’s
developmentally abnormal circuitry and reduced
neuroplasticity may lead to the cognitive and
behavioral deterioration seen during schizophrenia
onset and then continuing over the lifespan. In this
chapter, we review and consider current clinical
and neuropathological data that implicate abnormal
neurodevelopment and neuroplasticity in the patho-
genesis of schizophrenia, and highlight the potential
roles in these processes of several genes that have
been recently associated with the illness.
Clinical and epidemiological evidence supporting
aberrant neurodevelopment in schizophrenia
Epidemiological studies have identified a variety of
prenatal and perinatal factors conferring increased
risk for the later development of schizophrenia via
deleterious effects on brain development. Many
studies have found that winter and spring births are
5–8% more frequent among persons with schizo-
phrenia than the general population (Torrey et al.,
1997). How season of birth affects the brain and risk
for mental illness is not clear, although the leading
speculation is that infections, more common in winter
and spring, may affect brain development. Mednick
(1988) found an increased frequency of schizophrenia
in children of mothers who were in their second
trimester of pregnancy during the 1957 influenza
epidemic, although subsequent studies questioned
such an association (Brown and Susser, 2002).
Elevated maternal serum immunoglobulin levels
near birth (Buka et al., 2001), as well as increased
frequency of maternal rubella infection among
individuals who later develop schizophrenia (Brown
et al., 2001), have also been reported and suggest
a relationship with intrauterine infection.
Urban birth may be another epidemiological risk
factor for schizophrenia. Several studies have found
an increase in schizophrenia among those born in
urban environments (Marcelis et al., 1998; Mortensen
et al., 1999). The mechanism for this is not clear, but
possibilities include infectious disease, toxic expo-
sures, malnutrition, elevated density of families with
a history of mental illness in cities, or ill-defined
deleterious effects of growing up in an urban
environment. Severe maternal malnutrition has been
invoked in a study of children conceived during the
severe Dutch Hunger Winter of 1944–1945. Such
children had a two-fold increase in risk for
schizophrenia (Susser et al., 1996).
Perinatal and obstetrical complications may affect
the brain and have been associated with a higher risk
of schizophrenia. In a meta-analysis by Geddes and

Lawries (1995), the risk was two-fold. Among the
complications cited are hypoxemia (e.g., associated
with abnormal birth presentation, complicated
Caesarean section), perinatal viral exposure, pre-
maturity, and ABO blood type incompatibility.
A number of minor physical anomalies that are
more common in schizophrenia may be found in
association with developmental brain abnormalities
(O’Callaghan et al., 1991; Schiffman et al., 2002;
Gourion et al., 2004). The most obvious anomaly
is head circumference which is a direct correlate of
brain growth in neonates and children. Several
studies have reported decreased head circumference
at the time of birth in individuals who later develop
schizophrenia suggesting impaired or delayed brain
growth, although methodological issues in these
studies remain (McNeil et al., 1996; Cantor-Graae
et al., 1998; Cannon et al., 2002). Small adult head
circumference has been reported too, although this is
controversial and at best, subtle.
While not directly measuring the trajectory of
brain growth, ultimate brain volume is best measured
with magnetic resonance imaging, and there have
been numerous studies using this technology. Many
report increased volume of the lateral ventricles and/
or decreased volume of the superior temporal gyrus,
hippocampal formation, and parahippocampal gyrus
(McCarley et al., 1999; Talbot and Arnold, 2002;
Liddle and Pantelis, 2003). Reductions in gray matter
volume and in the volumes of the hippocampal
formation and parahippocampal gyrus have been
reported at first presentation before neuroleptic
treatment (Ohnuma et al., 1997; Gur et al., 1999;
Joyal et al., 2002). Volume changes are less
consistently found in other brain areas, including
the prefrontal cortex, cingulate gyrus, parietal lobe,
thalamus, basal ganglia, cerebellar vermis, and
olfactory bulbs (McCarley et al., 1999; Turetsky
et al., 2000b; Liddle and Pantelis, 2003).
The ectodermal germ layer gives rise to the brain
and spinal cord, as well as skin and its many external
physical features. The increased frequency of minor
physical anomalies in schizophrenia (O’Callaghan
et al., 1991; Schiffman et al., 2002; Gourion et al.,
2004), such as a high-arched palate, low-set ears,
anomalous skin ridge patterns, and curved fingers are
thought to derive from abnormal ectodermal devel-
opment and are seen in association with various
321
forms of mental retardation and other brain
disorders (Waldrop et al., 1968; Lohr and Flynn,
1993; Sivkov and Akabaliev, 2003).
A neurodevelopmental etiology of schizophrenia
is also supported by investigations of intellectual,
motor, and social development during childhood and
adolescence. Impaired language acquisition, lower IQ
scores, lower cognitive functioning, poor academic
achievement, and attention deficit disorder have been
found in both younger and older school-age children
who later develop schizophrenia in adolescence or
adulthood (Chua and Murray, 1996; Davidson et al.,
1999; Niemi et al., 2003). Motor abnormalities during
childhood associated with schizophrenia include
delayed development of sitting, standing, and
walking, as well as increased occurrence of unusual
movements such as choreoathetotic posturing (Fish
et al., 1992; Jones et al., 1994; Walker, 1994; Niemi
et al., 2003).
Lastly, abnormalities in social development during
childhood have been reported by a number of
investigators (Niemi et al., 2003). Among the social
adjustment anomalies described are a tendency to
play alone, poor social confidence, social anxiety,
social withdrawal, inappropriate and disruptive
social behaviors, fewer social relations, hypersensi-
tivity, and a paucity of dating experience (Done et al.,
1994; Jones et al., 1994; Malmberg et al., 1998; Olin
et al., 1998; Davidson et al., 1999; Niemi et al., 2003).
While these behaviors may reflect neurodevelopmen-
tal abnormalities that are inherent in the schizo-
phrenia disease process, they may also represent
environmental psychological stressors that foster the
development of mental illness. Our understanding of
the neural basis of social-affiliative behaviors is in its
infancy, but it is interesting to note that social-
affiliative behaviors are entering the field of research
as target behaviors in mouse models of schizophrenia
(Ellenbroek and Cools, 2000; Miyakawa et al., 2003).
Clinical evidence supporting aberrant neural
plasticity in schizophrenia
‘‘Neuroplasticity’’ is a broad term for any adaptive
changes in structure or function of the nervous
system during development, cognition, recovery from
injury, and aging. In our discussion of neural
322
plasticity in schizophrenia, we will use the term more
narrowly to refer to the molecular, chemical,
morphological, and physiological modifiability of
neurons and neurotransmission that occurs with
sensory and cognitive neural activity.
Sensation, perception, attention, memory, learn-
ing, and thought represent the diverse domains of
information processing in which deficits have been
reported in schizophrenia (Goldberg et al., 2003). The
deficits span sensory modalities and may reflect a
fundamental disturbance in neurobiological mecha-
nisms by which the brain responds to and changes
with environmental input. Within the context of
global cognitive impairments in schizophrenia,
specific deficits are found in attention, working
memory, executive function, and episodic memory
(Saykin et al., 1991; Goldberg et al., 2003). Several
brain systems are implicated by these deficits. The
attention processing circuitry is complex and includes
the prefrontal cortex and structures directly con-
nected with it, especially the posterior parietal cortex,
anterior cingulate gyrus, hippocampal formation,
and striatum (Fernandez-Duque and Posner, 2001;
Wall and Messier, 2001; Faw, 2003; Pessoa et al.,
2003; Saint-Cyr, 2003). Deficits in working and
episodic memory also implicate the prefrontal cortex
(Buckner et al., 2000; Faw, 2003) and its connec-
tions with the posterior parietal cortex, anterior
cingulate, temporal and parahippocampal cortices,
and striatum (Andres, 2003).
A particularly interesting sensory modality in
which deficits have been described in schizophrenia
is olfaction. Many studies over the last decade have
reported significant deficits in odor identification,
detection, memory, and hedonics (Moberg et al.,
1999; Moberg and Turetsky, 2003). From the
perspective of neuroplasticity, olfactory system
deficits may be especially instructive because they
could reflect abnormal dynamics in the ongoing
neurogenesis and synaptic turnover that distinguishes
the primary olfactory structures (olfactory epithelium
and bulb) from the rest of the brain (Schwob, 2002).
Initial studies have described abnormalities in the
lineage of olfactory epithelium neurons in schizo-
phrenia (Arnold et al., 2001).
Functional neuroimaging during activation by
cognitive or other neurobehavioral tasks has helped
define the pathophysiology of schizophrenia. Using
both positron emission tomography (Meyer-
Lindenberg et al., 2001; Abi-Dargham et al., 2002;
Buchsbaum et al., 2002; Potkin et al., 2002; Abi-
Dargham and Moore, 2003; Erritzoe et al., 2003;
Kim et al., 2003; Paradiso et al., 2003; Hazlett et al.,
2004) and functional MRI (Menon et al., 2001; Wible
et al., 2001; Gur et al., 2002; van Veen and Carter,
2002; Hofer et al., 2003; Jessen et al., 2003;
MacDonald and Carter, 2003; Weiss et al., 2003),
investigations have documented performance deficits
correlated with abnormal brain activation in the
ventromedial temporal lobe, prefrontal cortices,
limbic subcortical nuclei, and other brain regions
known to mediate memory, executive functioning,
attention, and emotional processing. These systems
are characterized by dynamic plasticity, a high degree
of interconnectivity and vulnerability to insult. If
fundamental mechanisms of structural, molecular, or
physiological plasticity are abnormal in schizophre-
nia, then these may be evident throughout the CNS,
but most prominent in the highly plastic neural
systems that mediate activity-dependent cognitive
processes such as attention, memory, and executive
functioning.
Electrophysiological studies have shown abnormal
information processing in schizophrenia by analyzing
event-related potentials (ERPs) triggered by sensory
stimuli. Such ERP abnormalities are common in the
disorder and include deficits in early preattentive as
well as late stages of information processing (Erwin
et al., 1998; Karoumi et al., 2000; Kathmann et al.,
2000; Fallgatter, 2001; Pekkonen et al., 2002;
McNeely et al., 2003; Turetsky et al., 2003;
Clementz et al., 2004). Aberrations in encoding of
input may reflect difficulty in screening out informa-
tion and inhibiting responses to irrelevant stimuli.
There may be corresponding deficits in response
facilitation to salient stimuli. Three ERP phenomena
have been the focus of investigation on successive
stages of stimulus processing and their neural
mechanisms. Failure of stimulus-induced inhibitory
processes is evident from studies of the P50 response
to paired clicks (Freedman et al., 1991; Erwin et al.,
1998) and on inhibition of an acoustic startle
response by a preceding sound (i.e., prepulse
inhibition) (Braff et al., 1992, 2001). In the paired
click paradigm, the amplitude of the P50 ERP to the
second of two auditory clicks is reduced in healthy

people, but not in individuals with schizophrenia.
Similarly, in the prepulse inhibition paradigm, the
startle response to a loud stimulus, preceded by a
low-intensity click, is reduced in controls, but not
patients. These two lines of research indicate a
fundamental neural failure to modify electrophysio-
logical response to a second stimulus paired to an
earlier one. Patients with schizophrenia also show
lower amplitudes of later ERPs, including the N200
during mismatch negativity conditions using deviant
tones on a passive background of tones (Hirayasu
et al., 1998; Williams et al., 2000; Brown et al., 2002)
and the P300 when attending to specified tones
(Turetsky et al., 1998a, b, 2000a; O’Donnell et al.,
1999). The ERP abnormalities suggest dysfunction of
the thalamus and hippocampus in the case of P50, the
superior temporal gyrus and perhaps hippocampus
and prefrontal cortex in the case of N200 mismatch
negativity, and inferior parietal cortex and probably
superior temporal gyrus, thalamus, and hippocampus
in the case of P300.
Neuropathological evidence indicating
abnormal neurodevelopment
While clinical and epidemiological findings present a
compelling case for the role of abnormal neurodevel-
opment in the etiology of schizophrenia, characteriz-
ing the cellular and molecular mechanism(s) by which
this might occur continues to present great
challenges. Neurons in the primate brain are born,
migrate, and assume their mature phenotype in a
complex and highly orchestrated process during
fetal development and early childhood period
(Nowakowski and Rakic, 1981; Arnold and
Trojanowski, 1996a, b; Hatten, 1999). By the time
the clinical expression of schizophrenia is apparent,
usually in the second or third decades of life,
neurogenesis and much of development is essentially
complete. While new neurons are generated in the
adult brain in certain areas (e.g., the dentate gyrus:
(Eriksson et al., 1998)), their number is small and
their similarity to perinatal neurons or their role in
neuroplasticity is still being ascertained (Eisch, 2002).
Neuropathologists have approached the challenge
of detecting neurodevelopmental anomalies in adult
brains in several ways. Some have focused on
323
cytoarchitecture, neuronal morphometry, and inner-
vation patterns in an ‘‘archaeological’’ manner to
infer the timing and nature of an abnormality in
neuronal migration, wiring, or other developmental
process from the anatomical appearance of the brain
at the time of death. In this manner, investigators
have reported a number of abnormalities in schizo-
phrenia, although most remain controversial.
Kovelman and Scheibel (1984) and later Conrad
et al. (1991) reported that pyramidal neurons within
the subfields of the hippocampus showed greater
variability in their axes of orientation. This dis-
organization in the normally uniform alignment of
neurons was interpreted as a developmentally based
disturbance of neuronal migration. However, several
attempts to replicate these findings with similar and
different methods have been unsuccessful (Altshuler
et al., 1987; Christison et al., 1989; Benes et al., 1991;
Arnold et al., 1995; Zaidel et al., 1997).
Abnormal neuronal migration during brain devel-
opment also was deduced from cytoarchitectural
studies of the entorhinal cortex, a limbic periallo-
cortex intimately related to the hippocampus (Witter
et al., 2000). Jakob and Beckmann (1986, 1989, 1994)
and then Arnold et al. (1991a) reported disturbed
cytoarchitectural differentiation, particularly in
superficial layers of the entorhinal cortex in schizo-
phrenia. However, others have reported no obvious
cytoarchitectural abnormalities in the entorhinal
cortex (Akil and Lewis, 1997; Krimer et al., 1997).
Quantitative cytoarchitectural studies have attempted
to avoid potential subjective bias inherent in
qualitative cytoarchitectural assessment, but these
too are conflicting. Falkai et al. (1988) found that
total neuron number in the entorhinal cortex was
reduced and there was evidence for abnormal clusters
of layer II neurons, but Krimer et al. (1997) reported
no alteration in neuronal numbers, density, or layer
volumes in any entorhinal sector, though they did
find a trend toward lower numbers and density in
almost all layers of the most rostral entorhinal
sectors. Arnold et al. (1997) applied spatial point
pattern analysis to interneuronal distances and found
subtle, but statistically significant differences in
clustering and dispersion indices of neuron position
in the entorhinal cortex. Similar approaches in other
corticolimbic regions (e.g., anterior cingulate cortex)
have revealed subtle cytoarchitectural differences
324

in schizophrenia compared to controls (Benes and
Bird, 1987; Benes et al., 1987, 1992a, 1992b, 1995;
Chana et al., 2003). Apparent loss of neuropil in the
absence of consistent neuronal loss suggests atrophy
or loss of synaptic connections between neurons
(Talbot and Arnold, 2002). That is consistent with
increasing indications that synaptic anomalies are
among the most common abnormalities in schizo-
phrenia (Benes, 2000; Mirnics et al., 2000) (Fig. 1).
Another cytoarchitectural approach has been to
map the number and position of interstitial white
matter neurons lying deep to cerebrocortical gray
matter. These neurons are considered to be remnants
of the cortical subplate and are thought to indicate
incomplete neuronal migration during brain develop-
ment. Furthermore, because the subplate is important
in directing the establishment of normal connectivity,
disturbance of the subplate could lead to altered
formation of connections. Several groups of investi-
gators reported abnormal numbers or positions of
neurons positive for NADPH-diaphorase or micro-
tubule-associated protein MAP2 within white matter
of frontal, temporal, and parahippocampal cortices in
schizophrenia, although the specific parameters of
maldistribution varied among studies (Akbarian et al.,
1993, 1996; Anderson et al., 1996; Kirkpatrick et al.,
1999; Rioux et al., 2003).
Although aberrant neuronal migration has been
the interpretation for most commonly invoked
cytoarchitectural abnormalities, there are other
possible explanations. The ultimate cytoarchitecture
of a given region is determined by complex
developmental and regressive neurobiological pro-
cesses. Many changes occur after migration. A host
of intrinsic signaling mechanisms responding to
extrinsic growth factors and neurotransmitters
influence neuron survival, morphology, neurite out-
growth, and patterns of synapse formation. Those
young neurons that fail to establish adequate
synaptic connectivity and access to trophic factors
do not survive. Furthermore, the spatial organization
of neurons depends not only on the number of
neurons that migrate to a particular position and
survive, but also the neuropil space in which those
neurons reside. Increases or decreases in this space
due to its many cellular (e.g., dendritic, axonal,
glial processes) and extracellular matrix constituents
will affect the spatial distribution of neurons. This
has been the interpretation of reports of reduc-
tions in neuropil in the dorsolateral prefrontal
cortex in schizophrenia (Selemon et al., 1998).
Finally, environmental factors during growth and
development (e.g., infection, ischemic injury,
trauma, etc.) as well as neurodegenerative changes

Fig. 1. Cytoarchitectural appearance of the entorhinal cortex from comparable rostral portions, with (a) nonpsychiatric control, and
(b) and (c) two schizophrenia subjects. Compared to the control, the entorhinal cortex in the schizophrenia subjects show subtle
alterations in the cellular composition and spatial arrangement of neurons in layers II and III. Note the poorly formed or absent
clusters of neurons in layer II and the more patchy distribution of neurons in layer III. The consistency of such findings across studies
has been controversial. Adapted from Arnold et al. (1997).

that are part of normal aging may further alter the
cytoarchitecture that is observed at postmortem
examination.
Investigators have examined the expression of
various proteins in adult postmortem brain tissues
that play critical roles in brain development. Among
those proteins is reelin, which plays an important role
in neuronal migration and maturation (Tissir and
Goffinet, 2003). Decreased reelin-positive cell num-
bers and lower reelin mRNA and protein expression
have been found by several research groups in
prefrontal cortex, hippocampus, and cerebellum
(Impagnatiello et al., 1998; Guidotti et al., 2000;
Fatemi et al., 2001; Eastwood and Harrison, 2003;
Eastwood et al., 2003). During embryogenesis, reelin
is an extracellular matrix protein secreted primarily
by Cajal–Retzius cells of the cortex that serves to
guide neuronal migration (Tissir and Goffinet, 2003),
stimulate dendritic spine maturation (Liu et al., 2001;
Pappas et al., 2001), and regulate synaptogenesis
(Sarnat and Flores-Sarnat, 2002). Murine or human
reelin mutations severely disrupt brain develop-
ment and result in lissencephaly, inverted cortical
lamination, abnormal axonal connectivity and
cerebellar hypoplasia (Pilz et al., 2002), which in
humans causes mental retardation, epilepsy, and
neurogenic hypotonia. In the adult, reelin continues
to be expressed primarily in GABAergic local
circuit neurons of the cortex and hippocampus
(Pesold et al., 1998). The function of reelin in the
adult nervous system is not known, but its
preferential expression in apposition to dendritic
spines suggests a possible role in dendritic plasticity
(Costa et al., 2001).
The Wnt protein/gene family is another example
of a development-related protein that has been
evaluated in schizophrenia. While the Wnt signaling
pathway is complex (Cox and Peifer, 1998), extra-
cellularly secreted Wnt binds to frizzled, a cell
membrane receptor that stimulates a complex
signaling cascade, ultimately suppressing the
constitutive activity of glycogen synthase kinase 3b
(GSK-3b). This prevents degradation of b-catenin
and leads to increased b-catenin-mediated gene
transcription of important developmentally regula-
tory genes. Wnt plays critical roles in many phases of
brain development, including neurogenesis, basic
patterning of the nervous system, axogenesis, axon
325
guidance, and synaptogenesis (Burden, 2000; Hall
et al., 2000; Coyle-Rink et al., 2002; Castelo-Branco
et al., 2003; Salinas, 2003). Investigations of the Wnt
signaling pathway in schizophrenia have produced
inconclusive findings so far, including reductions in
b- and g-catenins in the hippocampus (Cotter et al.,
1998), increased numbers of Wnt-1 immuno-
reactive neurons in the hippocampus (Miyaoka
et al., 1999), and decreased GSK3b, but normal
b-catenin in prefrontal cortex (Beasley et al., 2001)
while another study in a different cohort by the same
authors found no abnormalities in GSK3b (Beasley
et al., 2002).
Despite the early, conflicting findings, GSK-3 is
emerging as a candidate of great interest in
schizophrenia with respect to both neurodevelopment
and neuroplasticity (Kozlovsky et al., 2002). Aside
from its role in the Wnt signaling cascade, GSK-3a
and GSK-3b are at a nexus of other signaling
pathways, including the mitogen-activated protein
kinase (MAPK) and phosphatidyl-3 kinase (PI-3K)
pathways (Frame and Cohen, 2001; Doble and
Woodgett, 2003). Downstream, it has critical roles
in the phosphorylation of neural cell adhesion
molecule, synapsin-1, microtubule-associated protein
1B (MAP1B), MAP2, CREB, the glucocorticoid
receptor, and p53, which are variously involved in
neuronal migration, axon outgrowth and guidance,
dendrogenesis and arborization, spine formation and
remodeling, synaptogenesis and synapse functioning,
and programmed cell death. Decreases in GSK-3b
protein levels and enzyme activity have been reported
in schizophrenia in prefrontal cortex in two separate
brain collections (Kozlovsky et al., 2000; Beasley
et al., 2001; Kozlovsky et al., 2001) and we have
observed a significant decrease in the proportion of
GSK-3b immunoreactive neurons in the hippocam-
pus in our own collection (unpublished data). As
elaborated below, the GSK-3 pathway has addition-
ally been invoked in recent genetic association studies
of schizophrenia.
Neuropathological evidence indicating
abnormal synapses
It has been theorized that the bizarre thought
processes and cognitive dysfunction of schizophrenia
326
may result from ‘‘miswiring’’ or aberrant patterns or
integrity of synaptic connections in the brain. Also,
neuropsychological studies focused on learning and
memory and electrophysiological studies have
spawned notions of impaired plasticity and a
dysregulation of dynamic interactions within and
across brain systems (Frith and Done, 1988; Gray
et al., 1991; Friston, 1999; Breakspear et al., 2003).
Synapses have been investigated by a variety of
means in postmortem tissues in schizophrenia.
Ultrastructural studies have been rare due to the
technical confounds inherent in human neuropathol-
ogy research including agonal state and postmortem
delay effects on the physical integrity of the synaptic
complex. Nonetheless, while all ultrastructural find-
ings await replication, abnormalities have been
reported in the densities and aggregation of synapses
(Soustek, 1989; Aganova and Uranova, 1992; Kung
et al., 1998), dendritic spine morphology and
morphometry (Roberts et al., 1996; Kolomeets and
Uranova, 1999), axon terminal mitochondria
(Uranova et al., 1996; Kolomeets and Uranova,
1999), and various other changes in axospinous
densities and morphologies (for review, see Honer
et al., 2000).
Abnormalities in dendritic spines and arborization
also have been reported using Golgi impregnation
and immunohistochemical methods. Golgi studies
have described decreased spine densities in prefrontal
and temporal cortices and in the hippocampus
(Glantz and Lewis, 1995; Lewis and Glantz, 1997;
Garey et al., 1998; Rosoklija et al., 2000), decreased
densities of pyramidal basilar dendrites in prefrontal
cortex pyramidal neurons (Broadbelt et al., 2002) and
increased densities of dentate gyrus granule cell
basilar and recurrent dendrites (Lauer et al., 2003).
Another index of dendritic densities that has been
used in schizophrenia is immunolabeling for the
microtubule-associated protein MAP2 which is
selectively expressed in the somatodendritic domain
of neurons. Two studies reported a decrease in the
density of MAP2 expression in the hippocampus
(Arnold et al., 1991b; Rosoklija et al., 1995) while
another group found significant increases in MAP2
immunoreactive dendritic arborization in the hippo-
campus (Cotter et al., 2000). Future studies will need
to clarify the nature and extent of dendritic
abnormalities in schizophrenia.
The most commonly used method to assess
synaptic integrity in schizophrenia has been immuno-
chemistry of synapse-related proteins with Western
blotting, ELISA, or immunohistochemistry. Most
studies have focused on presynaptic proteins. Among
the proteins that have been examined are the synaptic
vesicle membrane, docking, and fusion proteins
synaptophysin, synapsin, SNAP25, complexins I
and II, rab3a, and syntaxin, as well as GAP43 and
NCAMs which are also highly expressed in axon
terminals. The regions most commonly examined
have been hippocampus, dorsolateral prefrontal
cortex, and anterior cingulate. While not without
controversy, most studies reported significant
decreases in presynaptic terminal markers (for
reviews, see Honer et al., 2000; Eastwood and
Harrison, 2001; Harrison and Eastwood, 2001).
Complementing the immunochemical studies
have been studies of presynaptic protein gene
expression with Northern, in situ hybridization,
RT-PCR and microarray analyses. Here too,
significant abnormalities of mRNA expression,
mostly decreases, have been reported (Honer et al.,
2000; Eastwood and Harrison, 2001; Harrison and
Eastwood, 2001).
Among the most interesting recent studies have
been the gene expression microarray experiments.
These have the capacity to examine the coordinated
expression of large numbers of genes and analyze
them by functional groups and pathways. The first
published microarray analysis of schizophrenia
Mirnics et al. (2000) reported a general down-
regulation of gene transcripts encoding proteins
involved in presynaptic function in the dorsolateral
prefrontal cortex in schizophrenia. The genes that
were most consistently downregulated were N-ethyl-
malemide sensitive factor (NSF), synapsin II,
synaptojanin I and synaptotagmin. In addition,
various genes involved in GABAergic and glutama-
tergic neurotransmission as well as a potentially
important signal transduction molecule (regulator of
G protein signaling 4 (RGS4)), and several G0
subunits were decreased in this cohort (Mirnics et al.,
2001). Hakak et al. (2001) used large oligonucleotide
microarrays to examine dorsolateral prefrontal cortex
in an elderly, highly chronic schizophrenia cohort.
While emphasizing abnormally decreased expression
of oligodendroglial genes (which also could
 327

importantly affect neural connectivity), they also

reported abnormalities in various presynaptic,
GABA, and postsynaptic signal transduction path-
way molecules, albeit with some findings in opposite
directions to those reported by Mirnics et al. The
bases for these discrepancies remain to be elucidated
and may be related to methodological differences in
samples, analytic strategies, or biological variability.
In another microarray study examining a more limi-
ted number of genes in pooled samples of prefrontal
cortex, cerebellum and midtemporal gyrus, Vawter
et al. (2001)reported significant decreases in a number
of genes related to synaptic signaling.
The three studies cited above examined gene
expression in tissue homogenates. In a more novel
approach, Hemby et al. (2002) used single cell
microdissection and antisense RNA amplification
with microarrays to generate an expression profile of
individual entorhinal cortex neurons (Fig. 2). After
immunohistochemical and morphological identifica-
tion in paraffin-embedded sections from elderly, Fig. 2. (a–b) Magnified portions of human gene discovery
microarray images (GDA; Genome Systems, Inc., St. Louis,
chronic subjects with schizophrenia and matched
MO, USA) after hybridization with control (a) and schizo-
controls, mRNA from individually microdissected phrenia (b) mRNA samples amplified from single entorhinal
stellate neurons in layer II of the entorhinal cortex was neurons. Gray arrows indicate site of SNAP-25, the hybridiza-
extracted and linearly amplified. The relative abun- tion intensity of which was decreased by 4.4 fold in
dance of mRNAs so obtained was determined using schizophrenia compared to control. (c) Graph depicts expres-
several cDNA microchip arrays. Over 25,000 genes sion levels using confirmatory reverse Northern blot analysis in
layer II–III entorhinal cortical neurons in control (black bars)
were assessed. Forced clustering of the data revealed and schizophrenia (gray bars) specimens for selected genes
marked differences between schizophrenia subjects including glutamate receptors, G-proteins, and synapse-related
and controls in mRNA expression of presynaptic proteins. Messenger RNA values correspond to hybridization
proteins (syntaxin, synaptotagmins, synaptic vesicle intensity for individual transcripts normalized to the total blot
hybridization intensity. Bars represent mean  SEM. Asterisks
amine transporter, SNAP-25, and g-adaptin), recep-
indicate p < 0.05. Adapted from Hemby et al. (2002).
tors (GABA-A, a-7 nicotinic, interleukin-2, retinoic
acid), ion channels (Naþ, Kþ, Cl
), and transcription
factors (e.g., fos, junB, PML-1, Brg, and Brm). by Kim et al. (1980) who noted decreased levels of
While many of the pre- and postsynaptic cerebrospinal fluid glutamate in schizophrenia, the
structural, protein and gene expression findings glutamate hypothesis of schizophrenia has garnered
require clarification and replication, all together, increasing support over the years (for reviews, see
neuropathological evidence provide substantial Grant, 2003; Konradi and Heckers, 2003). This
support for a central role of synaptic abnormalities hypothesis holds that hypofunctioning of the
in schizophrenia. glutamate system, and in particular, NMDA recep-
tors (with secondary increases in glutamate release
in some areas) gives rise to the positive, negative,
Neuropathological evidence indicating abnormal cognitive, and deteriorative features of schizophrenia
synaptic plasticity (Olney et al., 1999).
Apart from its important roles in synaptogenesis
Extensive data implicates dysregulation of the and synaptic toxicity/degeneration, it is well estab-
glutamate system in schizophrenia. First presented lished that one of the most important forms of
328
synaptic plasticity in higher cognition, long term
potentiation (LTP), is NMDA receptor mediated.
Activation of NMDA receptors leads to Caþþ influx,
activating Caþþ-dependent enzymes such as
CaMKII, which translocates to the nucleus to
phosphorylate the transcription factor CREB,
which leads to new protein synthesis important for
synaptic remodeling. Transgenic and knock-out
experiments in various species have demonstrated
the necessary role for CREB in the establishment
of long-term memory via LTP.
The NMDA receptor itself is just one component
of a complex multiprotein postsynaptic machinery
that mediates neurotransmission and plasticity.
Apart from the NMDA receptor, important compo-
nents of the postsynaptic density include the
scaffolding proteins PSD95, Shank, Homer,
GKAP, GRIP as well as AMPA and metabotropic
glutamate receptors (Sheng and Kim, 2000).
Postmortem studies have reported schizophrenia-
related abnormalities in the expression of a number
of NMDA receptor complex and related signal
transduction proteins, including the NR1, NR2A,
and NR28 receptor subunits, PSD95, SAP97,
SAP98, mGlur5, mGluR6, Erk1, MAPK phospha-
tase, and the excitatory amino acid transporter
EAAT2 (Grant, 2003). Altogether these findings
indicate substantial differences in the molecular
machinery of glutamate neurotransmission and
signal transduction and are consistent with a model
of impaired neuroplasticity in schizophrenia leading
to the learning and other cognitive deficits typical of
the disorder.
Genes recently associated with schizophrenia:
implications for neurodevelopment and
neuroplasticity
Genetic susceptibility plays an important role in the
pathogenesis of schizophrenia, the hereditability of
which is estimated to be 82–84% (Owen et al., 2002).
In a meta-analysis of whole genome scans, Lewis et al.
(2003) reported greater consistency of linkage results
across studies than had previously been recognized
and identified major susceptibility loci on chromo-
somes 1q, 3p, 5q, 6p, 8p, 11q, 14p, 20q, and 22q, with
somewhat weaker data for regions of 6q, 10p, 15q,
16q, 17q, and 18q.
In the last two years, associations between
schizophrenia and a number of specific genes have
been reported (for review, see Harrison and Owen,
2003 and O’Donovan et al., 2003. While some of
these have been replicated, others remain unrepli-
cated or controversial. Specific candidate genes for
schizophrenia now include those encoding, neuregu-
lin 1 (NRG1) (Stefansson et al., 2002, 2003a; Tang
et al., 2003a; Williams et al., 2003b; Yang et al.,
2003), dysbindin (i.e., dystrobrevin binding protein 1,
DTNBP1) (Straub et al., 2002; Schwab et al., 2003)
DISC-1 (Millar et al., 2000; Blackwood et al., 2001;
Devon et al., 2001; Millar et al., 2001; Hwu et al.,
2003), proline dehydrogenase (Jacquet et al., 2002;
Liu et al., 2002; Fan et al., 2003; Williams et al.,
2003a), G72/G30 (Chumakov et al., 2002; Hattori
et al., 2003), regulator of G-protein signaling-4
(RGS4) (Mirnics et al., 2001; Chowdari et al., 2002),
the D3 dopamine receptor (Jonsson et al., 2003),
D-amino acid oxidase (Chumakov et al., 2002),
catechol-O-methyl transferase (O’Donovan et al.,
2003), and AKT (Emamian et al., 2004). While
variations in each of these genes confers only modest
increases in risk for the disorder, their discovery
nonetheless identifies candidate proteins and mole-
cular pathways that may importantly contribute to
the pathophysiology of schizophrenia. This opens the
door to a functional genomics of schizophrenia. It is
noteworthy that most of these genes play important
roles in neurodevelopment, neurotransmission, or
neuroplasticity.
The data supporting the associations of
neuregulin-1, dysbindin, and AKT are among the
strongest. In the ensuing paragraphs, we will focus on
these three genes in schizophrenia and their functions
in neurodevelopment, functional synaptic connectiv-
ity, and neuroplasticity.
Neuregulin 1 (NRG1)
The first report on the linkage and association of
NRG1 to schizophrenia came from the studies of the
deCode Genetics group in the Icelandic population
(Stefansson et al., 2002). In a genome wide scan, the
authors found the highest multipoint LOD score of

greater than 3 on chromosome 8p, in a region
previously identified by other groups too (Lewis et al.,
2003). Extensive fine mapping of the 8p locus and
haplotype association analysis as well as the
transmission/disequilibrium test identified a highly
significant core haplotype consisting of five single
nucleotide polymorphisms (SNPs) and two micro-
satellite markers at the 50 end of the NRG1 gene
associated with schizophrenia. Since the initial report,
NRG1’s association with schizophrenia has been
replicated in several other populations, although no
functional mutations have yet been defined in the
gene (Stefansson et al., 2002, 2003a, b, 2004; Williams
et al., 2003b; Yang et al., 2003; Iwata et al., 2004;
Tang et al., 2004).
NRG1 has diverse functions in the CNS and thus
the sequence variations in NRG1 may have various
implications in relation to the pathophysiology of
schizophrenia (Buonanno and Fischbach, 2001). The
effects of NRG1 on N-methyl D-aspartate (NMDA)
receptors should be seen as a possible link to the
pathophysiology of schizophrenia, particularly in
light of the glutamatergic hypothesis of schizophrenia
(Konradi and Heckers, 2003). When NRG1 is
applied to cerebellar slices, NMDA receptor subunit
2C (NR2C) mRNAs increase 100-fold in granule
cells, suggesting that NRG1-erbB signaling directly
regulates glutamatergic neurotransmission (Ozaki
et al., 1997, 2000). In addition, NRG1 hypomorphic
mice exhibited abnormal prepulse inhibition of the
acoustic startle responses which is widely seen as an
endophenotype of schizophrenia. Interestingly,
clozapine treatment reduced hyperactive behaviors,
as it decreases the binding activities of NMDA
receptors. Altogether, this evidence suggests a
possible association between alterations in NRG1-
erbB signaling with the changes in glutamatergic
neurotransmission observable in schizophrenia.
NRG1 also affects neuronal development, migra-
tion, and survival. When NRG1 is blocked by
ribozyme-tRNA transgene technique in chick
embryos, the proliferation of neuroepithelial cells
and the differentiation of retinal ganglion neurons are
found to decrease (Bermingham-McDonogh et al.,
1996; Zhao and Lemke, 1998). In vitro, NRG1 has
been shown to support neurite outgrowth in various
cell lines (Vaskovsky et al., 2000), and also increase
neuronal survival and decrease apoptosis. In
329
addition, NRG1 modulates migration of neuronal
precursors as well as neuronal cells (Schmid et al.,
2003) and thus can provide a lead, considering that
abnormal migration of neurons has been implicated
for disturbed cytoarchitecture.
Another important role of NRG1 in the CNS is
in the development and survival of glial cells. In
transgenic mice with null mutations for erbB3 or
erbB2, receptors for NRG1, as well as in animals with
cre based conditional ablation of erbB2, there is a
dramatic lack of Schwann cells (Riethmacher et al.,
1997; Morris et al., 1999; Woldeyesus et al., 1999).
In cultured multipotent neural crest cells, NRG1
promotes the adoption of glial cell fate and
suppresses neuronal differentiation (Shah et al.,
1994; Shah and Anderson, 1997). NRG1 is also
required for the development of oligodendroglial
lineage. Recently, the density of oligodendrocytes
has been found to decrease in certain regions of post-
mortem brains of patients with schizophrenia (Hof
et al., 2002, 2003), which is in part corroborated in
microarray analyses (Hakak et al., 2001). Therefore,
it is possible that changes in NRG1 expression
contribute to oligodendrocyte abnormalities asso-
ciated with schizophrenia.
The nervous system is not just comprised of
neuron-neuron connections but also of robust cross
talks between neurons and glial cells (Haydon, 2001).
Trophic signaling between neurons and glia is
reciprocal and NRG1, released from both neurons
and glial cells, might play a key role in regulating
their interactions (Lemke, 2001). Thus, alterations in
NRG1 gene, such as in persons with the NRG1 high
risk haplotype, may not only result in the compro-
mised availability of NRG1 for trophic support for
neurons or glial cells, but may also alter interactive
signaling between these cells, leading to alterations
in their synaptic strength (Moises et al., 2002;
Falls, 2003).
Dysbindin-1
Dysbindin-1 is a 352 amino acid protein with a
predicted molecular mass of 40 kDa (Benson et al.,
2001). It contains a coiled-coil domain between
amino acids 88–177 believed to be the binding site
of dystrobrevins, the muscle protein myospryn
330
(Benson et al., 2003) and the proteins muted and
pallidin (Li et al., 2003b), which are important in
trafficking proteins to lysosome-related organelles.
Dysbindin-1 is encoded by a gene at chromosome
locus 6p22.3 in the human genome (Straub et al.,
2002). The dysbindin-1 gene and its protein are
widely expressed in the body, including the brain
(Benson et al., 2001; Talbot et al., 2004). The protein
is found in neuronal cell bodies of many brain areas
and is markedly enriched in a few presynaptic fields,
specifically those of the hippocampal formation,
striatum, substantia nigra, deep cerebellar nuclei,
inferior olive, and substantia gelatinosa of the spinal
cord (Arnold et al., 2003).
Interest in the protein escalated with the 2002
report that certain haplotypes of SNPs in the
dysbindin-1 gene are significantly associated with
schizophrenia (Straub et al., 2002). Within two years
of that discovery, the association of schizophrenia
with one or another dysbindin-1 haplotype (com-
posed of 3–8 SNPs) has been confirmed in large
populations from England (Datta et al., 2003; van
den Oord et al., 2003), Ireland (van den Oord et al.,
2003; Williams et al., 2003b), Wales (Williams et al.,
2003b), the Netherlands (Bakker et al., 2003),
Germany/Hungary/Israel (Schwab et al., 2003),
Sweden (Van Den Bogaert et al., 2003), China (Shi
et al., 2003; Tang et al., 2003), and Japan (Yamada
et al., 2003). Only two studies failed to replicate such
findings. One analyzed an Irish population (Morris
et al., 2003) in which subsequent analysis showed
that a different dysbindin haplotype (with a SNP in
the promoter region) actually was more common in
schizophrenia than in control cases (O’Donovan
et al., 2003; Williams et al., 2003c). The remaining
negative study on German and Polish populations
did not test haplotypes including the promoter SNP
(Van Den Bogaert et al., 2003). No other gene to date
has been associated with schizophrenia so frequently
and consistently.
Such findings led O’Donovan and his colleagues
(O’Donovan et al., 2003) to argue that the dysbindin-
1 gene is among the most promising genetic
susceptibility locus for schizophrenia. Indeed, two
groups recently reported abnormal dysbindin-1
protein expression in schizophrenia. Homogenate
studies on the prefrontal cortex found that dysbindin-
1 gene and protein expression were significantly
reduced by as much as 20% in about 40% of
schizophrenia cases compared to nonpsychiatric
controls (McClintock et al., 2003). Immunohisto-
chemical studies in the hippocampal formation found
that dysbindin-1 protein levels were significantly
reduced by as much as 42% in one or more
presynaptic fields of intrinsic glutamatergic connec-
tions in 93% of schizophrenia cases compared to
nonpsychiatric controls matched for age, sex,
cerebral hemisphere, type of fixative, and postmor-
tem interval (Talbot et al., 2004). The findings in the
dentate portion of the hippocampal formation were
replicated in an independent sample. No such
differences were found in bipolar or major depressive
comparison cases, though the latter showed a trend in
that direction. Morphometric analyses on our cases
revealed that the observed presynaptic dysbindin-1
reductions in the hippocampal formation were not
due to axon terminal loss. Nor were the reductions
readily attributed to neuroleptic effects, because
control tests on mice treated chronically with
haloperidol at therapeutic doses showed no effect
on immunoreactivity of dysbindin-1 in the hippo-
campal formation (Fig. 3).
The prefrontal cortex and hippocampal formation
expression studies suggest that dysbindin-1 reduc-
tions in the brain may be a common feature in
schizophrenia. Since the percentage of cases showing
such reductions in the hippocampal formation was
far higher than reported frequencies of dysbindin-1
haplotypes conferring elevated risk of schizophrenia
(Straub et al., 2002; Van Den Bogaert et al., 2003;
van den Oord et al., 2003), it seems likely that those
haplotypes are not the only factor contributing to the
reduced protein levels. That suggests important roles
for other genetic, as well as nongenetic factors
unknown at present. Among them may be neuro-
developmental factors affecting protein expression,
posttranslational modification, transport, and/or
degradation. Dysbindin-1 reductions may simply be
the common outcome of many factors increasing risk
of schizophrenia, whether they are genetic, neuro-
developmental, or environmental.
Our studies of dysbindin-1 reductions in the
hippocampal formation point to a role for the protein
in regulating glutamatergic transmission. As noted
above, we found significant reductions of dysbindin-1
in intrinsic glutamatergic connections throughout
 331

Fig. 3. Dysbindin-1 immunohistochemistry in human hippocampal formation with obvious decrease in dysbindin-1 expression in
many hippocampal sectors in the schizophrenia compared to its matched control. Higher magnifications on right of boxed region of
dentate gyrus shows severe deficit in schizophrenia case of dysbinin-1 protein expression in the granule cells and most notably the inner
molecular layer, an intrinsic glutamatergic terminal field emanating from mossy neurons of the hilus of the dentate gyrus. Adapted
from Talbot et al. (2004).

the hippocampal formation in schizophrenia, speci-
fically in hippocampal fields CA1-3, the subiculum,
and especially the dentate gyrus (Talbot et al., 2004).
In the core or hilus of the dentate gyrus are large
neurons intensely immunoreactive for dysbindin-1.
They innervate the inner molecular layer of the
dentate gyrus, where dysbindin-1 and vesicular
glutamate transporter-1 (VGluT-1) are coextensively
localized in axon terminals. That band of axon
terminals displayed a reduction in dysbindin-1 and a
significantly correlated increase in VGluT-1 in our
schizophrenia cases compared to matched controls. It
is possible then, that dysbindin-1 normally inhibits
glutamate transport into synaptic vesicles and
thereby regulates glutamatergic transmission in the
hippocampal formation. To test that hypothesis, we
have begun studies on sandy mice, which have a
deletion mutation in the dysbindin-1 gene causing
markedly reduced brain levels of dysbindin-1 (Li et al.,
2003b). Consistent with our hypothesis, preliminary
results indicate that sandy mice with the lowest levels
of dysbindin-1 (homozygous animals) have higher
VGluT-1 levels in the dentate gyrus than sandy
mice with higher dysbindin-1 levels (heterozygous
animals).
Altered glutamatergic neurotransmission in the
hippocampal formation can alter information flow
and neuroplasticity in that structure. Via their
glutamatergic output to the inner molecular layer of
the dentate gyrus, mossy cells positive for dysbindin-1
in the hilus of the gyrus can prime or recruit large
numbers of granule cells to respond to entorhinal
input (Jackson and Scharfman, 1996). Such cells do
so in a manner found to support long-term
332
potentiation in granule cells of the dentate gyrus
(Hetherington et al., 1994), which project promi-
nently to hippocampal field CA3. The pyramidal cells
positive for dysbindin-1 in CA3 are also gluta-
matergic and give rise to collateralized axons, some of
which terminate locally. Such recurrent collaterals
provide an excitatory feedback pathway in CA3,
impairment of which may contribute to the associa-
tive memory deficits observed in mice with a localized
deficit of NMDA receptors in CA3 (Nakazawa et al.,
2002). Other collaterals of CA3 pyramidal cells
(Schaffer collaterals) project to CA1, where their
output can induce long-term potentiation via
glutamatergic mechanisms (Petrozzino and Connor,
1994; Matthies et al., 1995). As with hilar DG
projections, then, reduction of dysbindin-1 observed
in CA3 projections may alter information processing
and diminish synaptic plasticity in the hippocampal
formation.
AKT1
AKT1 (v-akt murine thymoma viral oncogene
homolog 1), also known as protein kinase B, is one
of the most recently reported genes to be associated
with schizophrenia (Emamian et al., 2004). In
contrast to NRG1 or dysbindin-1 which were first
identified by fine mapping of known susceptibility
loci, the association of AKT1 with schizophrenia
was identified while examining general hypotheses
that protein kinases are altered in psychiatric disease.
In particular, it was found that important mood-
stabilizing psychotropic medications share a mecha-
nism of action that is dependent upon GSK-3, which
is regulated directly by AKT1 (Coyle and Duman,
2003).
Emamian et al. (2004) found that among a panel
of kinases involved in synaptic plasticity, AKT1
protein levels and levels of phosphorylation of one of
its major substrates, GSK-3b were significantly
decreased in lymphocytes from patients with schizo-
phrenia as well as in postmortem prefrontal and
hippocampal brain tissues from two independent
schizophrenia brain tissue collections. GSK3b
protein levels were unaltered. AKT1 and GSK3b
phosphorylation did not correlate with age, gender,
or postmortem interval and were not altered in
rodents that had been chronically treated with
haloperidol.
To further characterize AKT1’s role in schizo-
phrenia, the authors then examined whether certain
variants of the gene encoding AKT1 were preferen-
tially transmitted. They genotyped five SNPs at the
AKT1 locus in 268 affected families and identified
one 3 SNP haplotype that was preferentially
transmitted to probands with schizophrenia with a
ratio of 1.8:1 ( p ¼ 0.0006), as well as several other
multi-SNP haplotypes that were transmitted at lower
levels of significance. They then showed that the core
risk haplotype was associated with lower protein
levels of AKT1 in lymphocyte cell lines.
As a behavioral and pharmacological assay of
potential effects of AKT1 deficiency, the authors
examined prepulse inhibition of the acoustic startle
response in AKT1 knock-out mice. This is an index
of sensorimotor gating that is abnormal in schizo-
phrenia and which can be modeled in animals. While
there were no baseline differences between AKT1
deficient and wild-type mice for startle amplitude
or prepulse inhibition, the knock-out mice exhibi-
ted reduced prepulse inhibition when additionally
challenged with amphetamine, suggesting some impair-
ment in the integrity or pharmacological respon-
siveness of neural circuitry of sensorimotor gating.
AKT1 is a serine-threonine kinase that is a nexus
for many signal transduction pathways. It plays a
central role in many cellular processes including cell
proliferation, apoptosis, glucose metabolism, angio-
genesis, and cell motility (Brazil et al., 2002). AKT
is activated rapidly by extracellular factors such as
insulin and insulin-like growth factors, and intracel-
lular signals such as Ras. During embryogenesis,
AKT1 promotes cell proliferation and cell survival
in response to growth factors and stimuli that elicit
calcium influx (Dudek et al., 1997) and phosphory-
lates a number of proapoptotic proteins, thereby
suppressing death signals (Datta et al., 1999).
While found in a variety of peripheral tissues,
AKT is highly expressed in the central nervous
system. During embryogenesis it is required for axon
elongation and branching (Markus et al., 2002) and
plays a role in reelin-mediated migration of nascent
neurons to the cortex (Beffert et al., 2002). AKT
also is important in regulating metabolic path-
ways important for cell survival through the

neuregulin-mediated PI3 kinase signaling pathway
(Li et al., 2003a). That AKT is important in
regulating two other candidate molecules (reelin
and neuregulin) in schizophrenia raises the possibility
that multiple genes, each of small effect, may interact
to promote the development of schizophrenia.
AKT1 continues to play important roles in the
plasticity of the adult nervous system. Increased
phosphorylation of AKT has been reported in
response to LTP in the hippocampus and fear
conditioning in the hippocampus (Sanna et al., 2002)
and amygdala in rodents (Lin et al., 2001). AKT1 is
found in the synaptic plasma membrane and at lower
levels in the dendritic lipid raft and postsynaptic
density fractions of neuronal tissues (Asaki et al.,
2003). Here it is thought to play a role in a post-
synaptically localized protein synthesis system that
is one of the mechanisms of synaptic plasticity.
Postsynaptic protein synthesis allows local and rapid
synthesis of the key proteins required for dendritic
spine or postsynaptic density modifications that
occur with long-term memory, the late phase of
LTP or long-term depression, and trophic stimula-
tion (Kang and Schuman, 1996; Huber et al., 2000;
Akama and McEwen, 2003). AKT phosphorylates
the GABAA receptor that mediates fast inhibitory
synaptic transmission, increasing the density of
GABAA receptors and thereby increasing synaptic
strength (Wang et al., 2003). Finally, brain-derived
neurotrophic factor signaling phosphorylates AKT
in the hippocampus during spatial reference and
working memory formation (Mizuno et al., 2003).
Concluding remarks
This review has described clinical and neurobiological
data relevant to the concepts of schizophrenia as a
disorder of neurodevelopment with consequent
effects on connectivity, and ongoing neuroplasticity.
Exciting findings have emerged from application of
diverse methods to elucidate specific structural
abnormalities and identify candidate molecular
pathways pertinent to the pathogenesis and patho-
physiology of the illness. It is important, however, to
remain mindful of conceptual and practical limita-
tions, which must guide interpretation of the data
and inform future research strategies.
333
First, schizophrenia is clinically heterogeneous
and almost certainly etiologically heterogeneous,
resulting from interaction of what are probably
multiple genetic factors (each of variable effect) and
multiple environmental factors (each also of variable
effect). Different combinations of these factors may
culminate in the phenotype we classify as schizo-
phrenia. Investigations to date have had only modest
successes in accommodating heterogeneity in their
design and interpretation of data.
Second, schizophrenia typically cannot be diag-
nosed until the late teens or early twenties, when most
of the fundamental processes of brain development
are largely complete. Thus, we must infer anomalous
development based on observable features in the
adult. For cellular and molecular studies examining
the cytoarchitectural appearance and molecular
composition of the adult brain at the time of autopsy,
this occurs at least a few years after most
developmental events happened, and unless death is
unnaturally early (e.g., due to suicide), it usually
occurs decades after disease diagnosis.
Etiology is further obscured by the confounding
effects of age, medical and psychiatric comorbidity,
medication and other somatic treatments, environ-
mental stimulation, and in the case of neuropatho-
logical studies, agonal and postmortem influences on
cellular and molecular integrity. To varying degrees,
these limitations been addressed in the studies
reviewed above, and it is critical to remain vigilant
about them in interpreting the data.
Finally, to our knowledge, schizophrenia is a
uniquely human disease. Some animal models do
allow us to investigate isolated features of schizo-
phrenia (i.e., endophenotypes), including neurodevel-
opmental and neuroplastic aspects of these features.
But such models are partial, and none has yet been
identified or designed to truly encompass a sufficient
range of phenotypic abnormalities to mimic human
schizophrenia.
Even with these limitations, an increasingly strong
case is emerging for schizophrenia as a disease of
neurodevelopment, neural connectivity, and neuro-
plasticity in specific neural and neurochemical path-
ways. Especially noteworthy are converging data
from genetic association studies, molecular neuro-
pathology studies, and selective animal models that
explore the implications of candidate molecules.
334
Identification and confirmation of genetic suscep-
tibility loci (e.g., AKT1, dysbindin, GSK-3, neur-
egulin, and reelin) and of molecular mechanism their
proteins affect (e.g., glutamatergic neurotransmis-
sion) represent critical steps towards defining the
neurobiology of schizophrenia and perhaps ulti-
mately discovering means of preventing and treating
it more effectively.
Acknowledgments
Support for our work cited here was provided by the
National Institutes of Health (MH64045, MH55199,
AG10124, AG09215), the National Alliance for
Research on Schizophrenia and Depression and the
Stanley Foundation.
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