Introduction to the Special Section:
Myelin and oligodendrocyte abnormalities
Vahram Haroutunian and Kenneth L. Davis
Department of Psychiatry, The Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY, USA
A central tenet of modern views of the neurobiology of schizophrenia is that the symptoms of schizo-
phrenia arise from a failure of adequate communication between different brain regions and disruption of
the circuitry that underlies behaviour and perception. Historically this disconnectivity syndrome has been
approached from a neurotransmitter-based perspective. However, efficient communication between brain
circuits is also contingent on saltatory signal propagation and salubrious myelination of axons. The papers
in this Special Section examine the neuroanatomical and molecular biological evidence for abnormal
myelination and oligodendroglial function in schizophrenia through studies of post-mortem brain tissue
and animal model systems. The picture that emerges from the studies described suggests that although
schizophrenia is not characterized by gross abnormalities of white matter such as those evident in mul-
tiple sclerosis, it does involve a profound dysregulation of myelin-associated gene expression, reductions
in oligodendrocyte numbers, and marked abnormalities in the ultrastructure of myelin sheaths.
Received 9 October 2006; Reviewed 18 October 2006; Revised 20 October 2006; Accepted 12 November 2006
Key words: Gene expression, microarray, neuroanatomy, neuropathology, post-mortem, schizophrenia.
Schizophrenia, like most psychiatric disorders, is
complex in origin. It typically manifests itself in late
adolescence or early adult life with major, progressive
and usually irreversible deterioration from a previous
level of functioning. Neuropathological studies con-
ducted during the past century have described a
multitude of ‘soft’ abnormalities in many brain re-
gions, but they have failed to identify a ‘smoking
gun’. For the past 50 yr, neurotransmitter-based ap-
proaches have dominated research and treatment
strategies in schizophrenia. These approaches have
been guided almost entirely by the interpretation
of therapeutic responses to pharmacological agents
(dopamine- and serotonin-based approaches), or by
the similarities of symptoms produced by some
drugs of abuse (e.g. glutamate-based approaches)
to schizophrenia. Neurobiological studies of these
neurotransmitter systems in living subjects and in
post-mortem specimens have generally yielded am-
biguous or contradictory results or effect sizes that
have been smaller and less robust than the ideal. Thus,
although these neurotransmitter-based approaches
have led to very significant advances in treatment
efficacy and to equally great strides in our under-
standing of the neurobiology of dopamine, serotonin
and glutamate neurotransmitter systems, to date,
they have contributed less to our knowledge of the
underlying biology of schizophrenia and its aetiology.
During the past decade, purely neurotransmitter-
based models of schizophrenia have evolved into
systems biology and connectivity-based hypotheses
(Harrison and Weinberger, 2004; Stewart and Davis,
2004). Although these hypotheses have also invoked
neurotransmitter system abnormalities, they have
been informed by neuroimaging and neuropathology
studies and have emphasized the interplay of neuro-
transmitters within and between different brain re-
gions. Thus, the central tenet of this modern view has
been that symptoms of schizophrenia arise from a
failure of adequate communication between different
Address for correspondence: V. Haroutunian, Ph.D., Psychiatry,
Room 4F-33A, Bronx VA Medical Center, 130 West Kingsbridge Road,
Bronx, NY 10468, USA.
Tel.: 718-584-9000-6082Fax: 718-365-9622
International Journal of Neuropsychopharmacology (2007), 10, 499–502. Copyright f 2007 CINP
brain regions and disruption of the circuitry that
underlies behaviour and perception.
Disruption of brain circuitry and even abnormali-
ties in neurotransmitter function can be brought about
by a variety of more basic factors. These factors can
include, but are clearly not limited to, alterations in
synaptic functions, synaptic proteins and G-protein
coupling (Levitt et al., 2006; Mirnics et al., 2001),
changes in energy metabolism and metabolic function
(Middleton et al., 2002; Prabakaran et al., 2004), chal-
lenges to the structural integrity of central nervous
system cellular components (Rosoklija et al., 2000) and
alterations in the mechanisms that subserve signal
propagation, including myelination (Davis et al.,
White-matter and myelination abnormalities are
high among the processes that must be considered in
any hypothesis that posits abnormal communication
within specific brain circuits and between brain re-
gions. Initial studies of white matter by neuroimaging
techniques failed to reveal profound deficits, but sub-
sequent work with higher resolution methodologies
has unveiled significant, albeit subtle, reductions and
deficits (Wright et al., 2000). These studies and the
multiple roles and functions of the myelin-forming
glial constituents of the brain as they relate to schizo-
phrenia have been reviewed recently (Stewart and
Davis, 2004). More direct evidence for myelin-
associated abnormalities in schizophrenia came first
from broad-scale microarray gene expression stud-
ies (Hakak et al., 2001) that identified the down-
regulation of the expression of a family of genes
associated with myelination and oligodendrocyte
function. This initial finding was soon confirmed by
other investigators using similar and different tools
and independent subject cohorts (Dracheva et al.,
2006; Katsel et al., 2004; Stewart and Davis, 2004; see
also Tkachev et al., 2007 and Haroutunian et al., 2007
in this Special Section). These findings have been ex-
tended and supported further by MRI and protein-
based experiments (Dracheva et al., 2006; Flynn et al.,
2003), light microscopic studies of post-mortem speci-
mens (Hof et al., 2003; Orlovskaia et al., 2000; see also
Segal et al., 2007 in this Special Section), and electron
microscopic studies of the frontal cortex and the
caudate nucleus (Uranova et al., 2004; see also
Uranova et al., 2007 in this Special Section).
Developments in novel neurobiological techniques
and technologies have allowed close scrutiny of
many of these systems in post-mortem brain tissue
specimens from persons with schizophrenia. These
studies are now beginning to be reported and the
papers in this Special Section describe and review
some of these approaches and their initial results.
Interrogation of gene expression profiles in single
or multiple brain regions by high-throughput gene
microarray technologies and the use of metabolomic
techniques is the topic of three of the papers in this
Special Section (Haroutunian et al., 2007; Sokolov,
2007; Tkachev et al., 2007). The other three papers in
the Special Section take advantage of modern neuro-
anatomical methodologies to examine more closely the
central nervous system elements that may be affected
by some of the gene expression deficits described
in schizophrenia. One of these papers focuses on the
detection of myelin-tract abnormalities and their re-
lationship to cognitive function in post-mortem
human brain specimens from persons with schizo-
phrenia (Dwork et al., 2007), the second examines the
ultrastructure of myelin and oligodendrocytes in mul-
tiple brain regions in schizophrenia (Uranova et al.,
2007), and the third explores the neuroanatomical
consequences of the ablation of one of the myelin-
associated genes involved in schizophrenia in mouse
model systems (Segal et al., 2007).
The picture that emerges from the studies described
here suggests that although schizophrenia is not
characterized by gross abnormalities of white matter
such as those evident in multiple sclerosis, it does in-
volve a profound dysregulation of myelin-associated
gene expression, reductions in oligodendrocyte num-
bers, and marked abnormalities in the ultrastructure
of myelin sheaths. Since each myelinating oligoden-
drocyte myelinates as many as 40 axon segments
Rodriguez-Gabin, 2002), it is easy to envision how
changes in the number of oligodendrocytes, and/or in
the integrity of myelin sheaths, and/or axoglial con-
tacts can have a profound impact on signal propa-
gation and the integrity of neuronal circuits. This
picture of myelin-associated deficits influencing signal
propagation and signalling through neural circuits
that subserve emotion, cognition and thought pro-
cesses is entirely consistent with the symptoms of
schizophrenia and with the disconnectivity hypothesis
alluded to above. The findings elaborated in this
Special Section are also consistent with the view that
it is no longer tenable to think only in terms of
neuron–neuron connections but we must view con-
nectivity and communication within the brain as the
interplay between circuits where neurons and glia
form functional units and interact to affect information
processing (Haydon, 2001). This view makes it abun-
dantly clear that further elaboration of the myelin-
associated dysfunction in schizophrenia is imperative
to the understanding of not only the neuropsychiatric
500V. Haroutunian and K. L. Davis
consequences of myelin and oligodendroglial deficits,
but to the identification of the core factors that are re-
sponsible for these deficits and the development of
corrective therapeutic approaches.
The studies described here were supported by
MH066392 to K.L.D., MH064673 and VA Merit Review
and MIRECC to V.H., and by M01-RR-00071 to the
Mount Sinai School of Medicine.
Statement of Interest
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502V. Haroutunian and K. L. Davis