Utilizing the results of these studies in normal adult
and developing monkey, our third research strategy involves the generation
of testable hypotheses regarding the elements of DLPFC circuitry that
might be dysfunctional in schizophrenia. These hypotheses are then tested
in postmortem human brain specimens from subjects with schizophrenia,
normal comparison subjects and in subjects with a history of mood disorders.
These high quality tissue specimens are obtained from a large brain
bank of well-characterized subjects operated by the Program's NIMH Conte
Center for the Neuroscience of Mental Disorders. Parallel studies in
the auditory cortices of the superior temporal gyrus, focused on the
psychotic features of schizophrenia, are conducted in collaboration
with Program member Dr. Robert Sweet. In support of these studies, Dr.
Karl-Anton Dorph-Petersen provides consultation in unbiased experimental
design and analysis through the Program's Neurostereology Core.
The contribution of alterations in gene expression to
brain abnormalities in schizophrenia is explored using in situ hybridization,
real-time quantitative PCR and DNA microarrays in collaboration with
Drs. Monica Beneyto, Takanori Hashimoto, Karoly Mirnics and Etienne
Sibille. For each finding, we seek to place it in the context of cortical
circuitry. The contribution of genetic variants to these gene expression
changes are examined through candidate gene studies with Dr. Vish Nimgaonkar
and colleagues. Finally, the impact of psychotropic medications on the
neural circuits of interest is tested using the primate model system
in which animals are exposed to these medications in a manner that exactly
mimics their clinical use. Together, these studies are designed to define
the pathophysiological processes that give rise to the cognitive symptoms
of schizophrenia, thus identifying potential targets for novel therapeutic
interventions, and to determine the pathogenetic processes that produce
the brain abnormalities of schizophrenia, thus providing the rationale
for new types of preventative interventions. |
| Figure 1. Gene expression in the DLPFC of control
and schizophrenia subjects. Representative autoradiograms illustrating
the expression of BDNF (A, B), TrkB (C, D), TrkC (E, F), and GAD67 (G,
H) mRNAs in DLPFC area 9 of a control subject (A, C, E, G) and an age-,
sex-, and PMI-matched subject with schizophrenia (B, D, F, H). The densities
of hybridization signals are presented in a pseudocolor manner according
to the calibration scales (right) for each mRNA. Expression levels of
BDNF and TrkB mRNAs are reduced in the schizophrenia subject (B, D) compared
with the control subject (A, C), whereas TrkC mRNA expression levels appear
similar between the control (E) and schizophrenia (F) subjects. GAD67
mRNA expression is also reduced in the schizophrenia subject (H) compared
with the control subject (G). Solid and broken lines indicate the pial
surface and the border between gray matter and white matter, respectively.
Scale bars (in A, B), 1 mm. (Hashimoto T, Bergen SE, Nguyen, Q, Xu B,
Monteggia LM, Pierri JN, Sun Z, Sampson AR, Lewis DA: Relationship of
brain-derived neurotrophic factor and its receptor TrkB to altered inhibitory
prefrontal circuitry in schizophrenia. J Neurosci 25:372-383, 2005.) |
