Examining the “dys”- ordered schizophrenic brain

NEURO
letter
Genesis
Examining the “dys”- ordered schizophrenic
brain
Barrington Quarrie1
1
Duke University, Durham, North Carolina 27708
Correspondence should be addressed to Barrington Quarrie ([email protected])
Papaleo and colleagues (2010) examined the molecular
effects of a fairly new protein in the field, dysbindin, on
phenotypical changes relating to schizophrenia-like behavior and looked at its possible correlation with the wellknown dopamine hypothesis for schizophrenia.
“It’s almost as if a demon might have passed from one
host to another.” - John Nash
John Nash, the Nobel Prize winning mathematician,
refers to the tragic effects of schizophrenia, a debilitating mental illness that affects about 1% of the population (Strobel, 2005). As Nash hints, some of the prime
symptoms in the illness are psychosis (e.g., hallucinations
and delusions) and thought disorganization (Laruelle et
al., 2003). This brain dysfunction may be explained by the
dopamine (DA) hypothesis, which states that abnormal
behaviors associated with schizophrenia arise from an increase of DA signaling via D2 receptors in several brain
regions, particularly the prefrontal cortex (PFC) ( Ji et al.,
2009). This D2 postulation has driven researchers to elucidate the molecular pathways by which individuals with
seemingly normal, even great, mental capability like John
Nash can become delusional and lose their senses of reality.
In the past five years, researchers have discovered the
dysbindin protein, promising for its possible associations
with schizophrenia. The dysbindin protein is localized
near synaptic sites in the PFC and may be involved with
presynaptic, DA vesicle trafficking ( Ji et al., 2009) as well
as postsynaptic, D2 receptor internalization (Iizuka et al.,
2007). Further research is necessary, however, to determine
the molecular and cellular effects of dysbindin on the expression of schizophrenia-like behavior.
Papaleo and colleagues have explored the effects of
dysbindin by performing cognitive, emotional, and physiological experiments in the mouse. They utilized knockout mice with an inactivated dysbindin gene and chronic
D2 agonist treatment to examine the role of dysbindin in
modulating PFC DA signaling. This model may provide
evidence for an individualized drug treatment target in
schizophrenic patients (Figure 1).
Because working memory deficits correlate with schizophrenia and DA functioning in the PFC (Vijayraghavan
et al., 2007), Papaleo et al. first analyzed the
working memory of dysbindin knockout mice. With use
of a T-maze paradigm under demanding conditions (i.e.,
increased number of trials with fewer time intervals),
they discovered that knockout mice (dys -/-) performed
worse than heterozygous dysbindin gene mice (dys +/-)
and worse than the wild-type mice (dys +/+). These results
indicate that reduced levels of dysbindin impairs working
memory under stressful situations, which correlates with
schizophrenia-like behavior. In addition, knockout mice
exhibited increased stress reactivity but, surprisingly, increased pre-pulse inhibition–a weak initial stimulus stops
a neurobiological reaction to a later stronger stimulus. The
latter finding presents an anomaly to previously tested
schizophrenia-like models and necessitates further inquiry.
Since dysfunctional working memory is associated with
the PFC and prior research has localized dysbindin to this
anterior, cortical region, Papaleo and colleagues further
Figure 1: Model
Dysbindin plays an important role in influencing prefrontal cortex (PFC)
functioning through modulation of D2 receptor activation and of CaMK
components in the DA signaling pathway, ultimately affecting schizophrenia-like behavior
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NEURO
Genesis
examined the pyramidal neurons within layer II/III of the
medial PFC (mPFC). The mPFC is critical for the formation of cognitive networks as well as DA modulation
and thus an appropriate region of interest to determine
whether varying levels of dysbindin differentially affects
neuronal excitability. With use of whole-cell current clamp
recording, it was found that pyramidal neurons were more
excited in null dysbindin mice relative to wild-type mice,
suggesting that reduced dysbindin levels may affect the
excitability of the pyramidal neurons in the PFC (Papaleo
et al., 2010).
Ca2+/calmodulin kinase (CaMK) components are
involved in working memory and DA regulation of the
neuronal excitability in this region (Gonzalez-Islas et al.,
2003, Runyan et al., 2005). When researchers examined
dysbindin’s connection with CaMK, it was found that null
mice had lower levels of CaMK, suggesting that dysbindin
may also influence the excitability of pyramidal neurons
through CaMK modulation.
Although these results show a phenotypical connection
to dysbindin, the underlying mechanism is still in question. Based on prior research documenting dysbindin’s
connection with dopamine, however, Papaleo and colleagues (2010) examined the possible influence of dysbindin on schizophrenic-like behavior through regulation of
DA signaling. Chronic drug treatment studies with quinpirole, a D2 agonist, were conducted to determine whether
mimicking increased DA signaling correlates with results
observed in null dysbindin mice. Pyramidal neurons in
the null dysbindin mice were shown to be more sensitive
to acute D2 receptor activation compared to wild-type,
which indicates a possible increased amount of D2 receptors on the surface of the neurons. Using the same experimental protocol, the researchers also used the chronic D2
receptor stimulation model to test another group of wildtype mice. Relative to wild type mice, quinpirole–treated
mice performed poorly on the more demanding T-maze
paradigm and exhibited increased pre-pulsed inhibition
and decreased CaMK levels, which correlate with the results seen in the null dysbindin mice. These similar results
suggest that the schizophrenia-like behavior seen with reduced dysbindin correlates with increased DA signaling.
Moving forward, questions regarding dysbindin’s role
in the biological mechanism underlying schizophrenia
have yet to be answered. The most obvious question is why
there is an increase of pre-pulse inhibition seen in both the
null dysbindin and quinpirole-treated mice. Although the
researchers argue that it may be caused by a change in sensitization, more research needs to examine this abnormality in the results. In addition, the pathway through which
DA signaling modulates the excitability of pyramidal neurons in mPFC layer II/III needs to be explored. Previous
research has shown inhibitory effects on the PFC pyramidal neurons via D2 activation (Vijayraghavan et al., 2007).
While enhanced baseline excitability in PFC pyramidal
neurons result from a decrease in dysbindin (Papaleo et al.,
2010), the mechanism by which this occurs has not been
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uncovered because of experimental constrains.
Overall, the implication behind these results is that dysbindin plays an important role in influencing PFC functioning through the modulation of D2 receptor activation
and CaMK components in the DA signaling pathway,
which ultimately affect schizophrenia-like behavior. Current research supports that dysbindin critically influences
PFC function through modulation of D2 receptor activation and CaMK components in the DA signaling pathway, which is implicated in schizophrenia-like behavior.
This present study indicates that genetic variations within
DTNBP-1(the dysbindin-encoding gene) may be genetic
marker for schizophrenia risk. A deeper investigation of
the mechanisms by which dysbindin interacts with various
biological molecular structures may unveil how dopaminergic signaling can be regulated to normalize PFC function. Such an understanding may facilitate pharmaceutical
or psychiatric treatment research for schizophrenia.
Gonzalez-Islas, C., and Hablitz, J.J. (2003). Dopamine enhances EPSCs in
layer II-III pyramidal neurons in rat prefrontal cortex. J Neurosci 23,
867-875.
Iizuka, Y., Sei, Y., Weinberger, D.R., and Straub, R.E. (2007). Evidence that
the BLOC-1 protein dysbindin modulates dopamine D2 receptor internalization and signaling but not D1 internalization. J Neurosci 27,
12390-12395.
Ji, Y., Yang, F., Papaleo, F., Wang, H.X., Gao, W.J., Weinberger, D.R., and
Lu, B. (2009). Role of dysbindin in dopamine receptor trafficking and
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Laruelle, M., Kegeles, L.S., and Abi-Dargham, A. (2003). Glutamate, dopamine, and schizophrenia: from pathophysiology to treatment. Ann N Y
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Papaleo, F., Yang, F., Garcia, S., Chen, J., Lu, B., Crawley, J.N., and Weinberger, D.R. (2010). Dysbindin-1 modulates prefrontal cortical activity
and schizophrenia-like behaviors via dopamine/D2 pathways. Mol Psychiatry, 1-14.
Runyan, J.D., Moore, A.N., and Dash, P.K. (2005). A role for prefrontal
calcium-sensitive protein phosphatase and kinase activities in working
memory. Learn Mem 12, 103-110.
Strobel, G. (Interviewer) & Murray, Robin. (Interviewee). (2005). Schizophrenia Research Forum [Interview transcript]. Retrieved from Schizophrenia Research Forum Web site: http://www.schizophreniaforum.org/
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Vijayraghavan, S., Wang, M., Birnbaum, S.G., Williams, G.V., and Arnsten,
A.F. (2007). Inverted-U dopamine D1 receptor actions on prefrontal
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