Deficient hippocampal neuron expression of proteasome, ubiquitin, and mitochondrial genes in multiple schizophrenia cohorts.
BACKGROUND
Hippocampal dentate granule neurons are altered in schizophrenia, but it is unknown if their gene expressions change in schizophrenia or other psychiatric diseases.


METHODS
Laser-captured dentate granule neurons from two groups of schizophrenia and control cases and from major depression and bipolar disease cases were examined for alterations in gene expression using complementary DNA (cDNA) microarrays and reverse transcription polymerase chain reaction (RT-PCR).


RESULTS
Compared with 24 control cases, the 22 schizophrenia patients in both groups revealed decreases in clusters of genes that encode for protein turnover (proteasome subunits and ubiquitin), mitochondrial oxidative energy metabolism (isocitrate, lactate, malate, nicotinamide adenine dinucleotide [NADH], and succinate dehydrogenases; cytochrome C oxidase; adenosine triphosphate [ATP] synthase), and genes associated with neurite outgrowth, cytoskeletal proteins, and synapse plasticity. These changes were not obtained in 9 bipolar cases or 10 major depression cases and were not associated with age, sex, brain weight, body weight, postmortem interval, or drug history. Brain pH contributed to the variance of some genes but was mostly independent of the disease effect.


CONCLUSIONS
Decreases in hippocampal neuron gene expression are consistent with brain imaging and microarray studies of the frontal cortex in schizophrenia. A mitochondrial and ubiquitin-proteasome hypofunctioning of dentate granule neurons may contribute to the deficits of schizophrenia.
Altar
C Anthony
CA
Psychiatric Genomics, Inc., Gaithersburg, Maryland 20878, USA. taltar@psygenomics.com
Jurata
Linda W
LW
Charles
Vin
V
Lemire
Andrew
A
Liu
Peng
P
Bukhman
Yury
Y
Young
Theresa A
TA
Bullard
Jeff
J
Yokoe
Hiroko
H
Webster
Maree J
MJ
Knable
Michael B
MB
Brockman
Jeffrey A
JA
D000704:Analysis of Variance; D001714:Bipolar Disorder / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D004272:DNA, Mitochondrial / Q000032:analysis; D018891:Dentate Gyrus / Q000378:metabolism* / Q000473:pathology; D003865:Major Depressive Disorder / Q000235:genetics / Q000378:metabolism; D045222:Electron Transport Chain Complex Proteins / Q000235:genetics / Q000378:metabolism; D004734:Energy Metabolism / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism*; D012720:Severity of Illness Index; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*
D004272:DNA, Mitochondrial; D045222:Electron Transport Chain Complex Proteins; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex