Alteration
of mitochondrial function in the hippocampus of
bipolar disorder patients
Recurrent
episodes of depression and either mania or
hypomania are the clinical features of bipolar
disorder. Although studies have reported a high
degree of heritability and linkage to
chromosomal loci, the disease mechanisms are
unknown. Recently abnormal mitochondrial energy
metabolism in the frontal and temporal lobes of
patients suffering from bipolar disorder has
been demonstrated. The aim of a the present
study was to determine the degree of expression
of 12,558 nuclear genes in the hippocampus in
subjects with bipolar disorder in comparison
with healthy controls and schizophrenic
patients.
Brains obtained postmortem from 10 healthy
controls, 9 patients with bipolar disorder, and
8 subjects with schizophrenia, were dissected to
isolate the hippocampus which was subsequently
sliced. Tissue preparation and
RNA extraction were performed and
expression of mRNA expression was studied
using gene arrays. Real-time quantitative
polymerase chain reaction assay allowed data to
be verified.
The expression of 43 nuclear genes was
significantly decreased in bipolar disorder but
not in schizophrenia, 18 of which (42%) coded
for mitochondrial proteins. More precisely this
reduction in gene expression concerned the
regulation of oxidative phosphorylation and the
adenosine triphosphate-dependent process of
proteasome degradation. Other genes were
involved in neurotransmission with decreased
expression of glutamic acid decarboxylase, the
enzyme synthesizing the inhibitory
neurotransmitter, g-aminobutyric
acid (GABA). The mRNA coding for the
neuropeptide, somatostatin, was also
decreased.
These results provide novel evidence for
abnormal mitochondrial energy metabolism in
bipolar disorder patients, which can lead to
increased lactate levels, glutamate
excitotoxicity, and apoptosis. Reduced
expression of genes coding for proteins of the
proteasome system can also have other negative
consequences such as, an impairment of synapse
remodeling. These two-levels of deficit could
represent potential targets for new compounds
for the treatment of bipolar disorder.
Konradi
C, Eaton M, MacDonald ML, Walsh J, Benes FM,
Heckers S. Molecular evidence for mitochondrial
dysfunction in bipolar disorder. Arch Gen
Psychiatry 61: 300-308, 2004.