ABERRANT GENE
EXPRESSION IN HIPPOCAMPAL DENTATE GRANULE AND CA3 NEURONS IN MULTIPLE GROUPS OF
SCHIZOPHRENIC PATIENTS
C.A.
Altar, L. Jurata, Y. Bukhman, T.A. Young, J. Bullard H. Yokoe, A. Lemire, M.B.
Knable1 M.J. Webster2, J.A. Brockman and V. Charles
Psychiatric Genomics, Inc., Gaithersburg MD, 20878
1Stanley
Medical Research Institute, Bethesda, MD; 3Uniformed Services
University Health Sciences, Bethesda, MD
Several
laboratories have identified small (<50%) and mostly non-overlapping gene changes in the brains of schizophrenic patients. These findings may be explained by the almost exclusive use of frontal cortex blocks, in which cellular heterogeneity could mask transcript changes in particular cell groups. Hippocampal neurons were obtained using laser-capture microdissection of frozen brain sections from two cohorts, each containing normal controls and patients with schizophrenia. One cohort also contained patients with bipolar disease or major depressive disorder. Amplified RNA obtained from ~2000-3000 dentate granule (DG) or CA3 neurons per patient was labeled with cyanine dye and hybridized to Agilent Human 1 cDNA microarray chips.
Statistically significant changes in gene expression revealed by microarrays
showed 3.2 fold and 2.4 fold more gene changes than would be expected by chance
in the DG of the schizophrenics from cohorts 1 and 2, respectively (n=8 and 14)
relative to controls (n=9 and 15). Overlaps between the cohorts in increasing
and decreasing genes of36% and 28%, respectively, were about 5- to 7-fold more
than would be expected by chance. The fact that ~90% of the overlapping genes
changed in the same directions increases the confidence in these findings. Gene
expression decreases outnumbered increases by 2:1, and changes were independent
of medication history, post-mortem interval, sex, pH and a variety of other
demographic factors. Both groups of schizophrenic cohorts revealed decreases in
genes involved in synaptic transmission, neuronal signaling, vesicular and
axonal transport and neurite outgrowth. Remarkably, 19 genes that encode for a
single macromolecular complex and 15 genes that encode for components of a
cellular organelle were also decreased, generating p values of at least 10-3
and 10-7 for each complex.
Many
similar gene changes were found in the CA3 neuron targets of dentate gyrus
neurons. Some of the same genes involved in synaptic function, neuronal
signaling and vesicular transport that were decreased in schizophrenia were
significantly increased in rats (N=10/group) treated with common
antipsychotic medications. The disease specificity of these changes was
evidenced by the finding of far fewer and mostly non-overlapping gene changes in
dentate neurons of patients with bipolar disease (n=9) or depression (n=10).
The
present results demonstrate the ability to isolate discrete populations of human
CNS neurons using laser-capture microdissection. As wit studies using brain
blocks, most studies, reproducible changes in large aggregates of highly-related
genes were identified in two schizophrenia disease cohorts. Because the
decreased expression of genes involved in synaptic structure, transmission and
transport are similar to those functions reported to be decreased in the
prefrontal cortex, such changes may contribute to the etiology of schizophrenia
and help identify potential targets for therapeutic intervention