Alterations in the neuropeptide galanin system in major depressive disorder involve levels of transcripts, methylation, and peptide

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, GAL 1-3 , 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 GAL 3 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.epigenetics | human postmortem brain | neuropeptides | stress | transmitter coexistence

Expression of galanin and its receptors are perturbed in a rodent model of mild, blast-induced traumatic brain injury

“…This phenotype could be rescued by knocking down expression of this receptor. This is further underscored by recent findings showing increased GalR1 levels (measured by qPCR) in the DRN/vPAG in human depressed suicides versus controls (Barde et al, 2016). These results lend further weight to the present findings observed in the mbTBI.…”

“…For the Ribo-ISH the sectioned tissues were first fixed for 10 min in cold 4% paraformaldehyde in 0.1 M sodium phosphate buffer (PBS), pH 7.4, followed by 5 The optimal exposure time was determined by exposing the slides to imaging plates (BAS-SR Fujifilm, Tokyo, Japan) for 24 h at RT, which were scanned using a phosphoimager (Fuji BAS 3000, Tokyo, Japan). Based on this data, TPH2 slides were developed after 72 h, galanin and TH typically after one week, and GalR1 after 8-12 weeks using D19 developer (Kodak) and AL-4 fixative (Kodak) and mounted in glycerolphosphate buffer.…”

Fibroblast growth factor 2 regulates activity and gene expression of human post‐mitotic excitatory neurons

“…Human genetic studies have shown the involvement of the galanin system in pshychiatric disorders and MDD (Barde et al . ). GAL and GALR1 have CRE binding sites (Zachariou et al .…”

Hypothalamic CNTF volume transmission shapes cortical noradrenergic excitability upon acute stress

“…Even if these neuroactive substances were ubiquitously co‐released, then the receptor repertoire of their cellular targets could diversify their action. Ultimately, ependymal cells could thus produce temporary neuropeptide constellations for volume transmission whose differential binding and output modulation in nearby midbrain and hindbrain structures could account for substantial functional heterogeneity and explain key features of neuropeptide contributions to anxiety and depression (Belzung et al , 2006; Barde et al , 2016). …”