Abstract:
Major depressive disorder (MDD) is a substantial burden to
patients, families, and society, but many patients cannot be
treated adequately. Rodent experiments suggest that the
neuropeptide galanin (GAL) and its three G protein-coupled
receptors, GAL1–3, are involved in mood regulation. To explore
the translational potential of these results, we assessed the
transcript levels (by quantitative PCR), DNA methylation status
(by bisulfite pyrosequencing), and GAL peptide by RIA of the GAL
system in postmortem brains from depressed persons who had
committed suicide and controls. Transcripts for all four members
were detected and showed marked regional variations, GAL and
galanin receptor 1 (GALR1) being most abundant. Striking
increases in GAL and GALR3 mRNA levels, especially in the
noradrenergic locus coeruleus and the dorsal raphe nucleus, in
parallel with decreased DNA methylation, were found in both male
and female suicide subjects as compared with controls. In
contrast, GAL and GALR3 transcript levels were decreased, GALR1
was increased, and DNA methylation was increased in the
dorsolateral prefrontal cortex of male suicide subjects,
however, there were no changes in the anterior cingulate cortex.
Thus, GAL and its receptor GALR3 are differentially methylated
and expressed in brains of MDD subjects in a region- and sex-
specific manner. Such an epigenetic modification in GALR3, a
hyperpolarizing receptor, might contribute to the dysregulation
of noradrenergic and serotonergic neurons implicated in the
pathogenesis of MDD. Thus, one may speculate that a GAL3
antagonist could have antidepressant properties by disinhibiting
the firing of these neurons, resulting in increased release of
noradrenaline and serotonin in forebrain areas involved in mood
regulation.
