Altered Organization of GABAA Receptor mRNA Expression in the Depressed Suicide Brain

Inter-relationships ordinarily exist between mRNA expression of GABAA subunits in the frontopolar cortex (FPC) of individuals that had died suddenly from causes other than suicide. However, these correlations were largely absent in persons that had died by suicide. In the present investigation, these findings were extended by examining GABAA receptor expression patterns (of controls and depressed individuals that died by suicide) in the orbital frontal cortex (OFC), hippocampus, amygdala. locus coeruleus (LC) and paraventricular nucleus (PVN), all of which have been implicated in either depression, anxiety or stress responsivity. Using QPCR analysis, we found that in controls the inter-relations between GABAA subunits varied across brain regions, being high in the hippocampus and amygdala, intermediate in the LC, and low in the OFC and PVN. The GABAA subunit inter-relations were markedly different in persons that died by suicide, being reduced in hippocampus and amygdala, stable in the LC, but more coordinated in the OFC and to some extent in the PVN. It seems that altered brain region-specific inhibitory signaling, stemming from altered GABAA subunit coordination, are associated with depression/suicide. Although, it is unknown whether GABAA subunit re-organization was specifically tied to depression, suicide, or the accompanying distress, these data show that the coordinated expression of this transcriptome does vary depending on brain region and is plastic

Molecular pathway reconstruction and analysis of disturbed gene expression in depressed individuals who died by suicide

Molecular mechanisms behind the etiology and pathophysiology of major depressive disorder and suicide remain largely unknown. Recent molecular studies of expression of serotonin, GABA and CRH receptors in various brain regions have demonstrated that molecular factors may contribute to the development of depressive disorder and suicide behaviour. Here, we used microarray analysis to examine the expression of genes in brain tissue (frontopolar cortex) of individuals who had been diagnosed with major depressive disorder and died by suicide, and those who had died suddenly without a history of depression. We analyzed the list of differentially expressed genes using pathway analysis, which is an assumption-free approach to analyze microarray data. Our analysis revealed that the differentially expressed genes formed functional networks that were implicated in cell to cell signaling related to synapse maturation, neuronal growth and neuronal complexity. We further validated these data by randomly choosing (100 times) similarly sized gene lists and subjecting these lists to the same analyses. Random gene lists did not provide highly connected gene networks like those generated by the differentially expressed list derived from our samples. We also found through correlational analysis that the gene expression of control participants was more highly coordinated than in the MDD/suicide group. These data suggest that among depressed individuals who died by suicide, wide ranging perturbations of gene expression exist that are critical for normal synaptic connectively, morphology and cell to cell communication

Decrease in REM latency and changes in sleep quality parallel serotonergic damage and recovery after MDMA: a longitudinal study over 180 days

The recreational drug ecstasy [3,4-methylenedioxymethamphetamine (MDMA)], has been found to selectively damage brain serotonin neurons in experimental animals, and probably in human MDMA users, but detailed morphometric analyses and parallel functional measures during damage and recovery are missing. Since there is evidence that serotonin regulates sleep, we have compared serotonergic markers parallel with detailed analysis of sleep patterns at three time-points within 180 d after a single dose of 15 mg/kg MDMA in male Dark Agouti rats. At 7 d and 21 d after MDMA treatment, significant (30-40%), widespread reductions in serotonin transporter (5-HTT) density were detected in the cerebral cortex, hippocampus, most parts of the hypothalamus, and some of the brainstem nuclei. With the exception of the hippocampus, general recovery was observed in the brain 180 d after treatment. Transient increases followed by decreases were detected in 5-HTT mRNA expression of dorsal and median raphe nuclei at 7 d and 21 d after the treatment. Significant reductions in rapid eye movement (REM) sleep latency, increases in delta power spectra in non-rapid eye movement sleep and increased fragmentation of sleep were also detected, but all these alterations disappeared by the 180th day. The present data provide evidence for long-term, albeit, except for the hippocampus, transient changes in the terminal and cellular regions of the serotonergic system after this drug. Reduced REM latency and increased sleep fragmentation are the most characteristic alterations of sleep consistently described in depression using EEG sleep polygraphy

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

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

Expression patterns of corticotropin-releasing factor, arginine vasopressin, histidine decarboxylase, melanin-concentrating hormone, and orexin genes in the human hypothalamus

The hypothalamus regulates numerous autonomic responses and behaviors. The neuroactive substances corticotropin-releasing factor (CRF), arginine-vasopressin (AVP), histidine decarboxylase (HDC), melanin-concentrating hormone (MCH), and orexin/hypocretins (ORX) produced in the hypothalamus mediate a subset of these processes. Although the expression patterns of these genes have been well studied in rodents, less is known about them in humans. We combined classical histological techniques with in situ hybridization histochemistry to produce both 2D and 3D images and to visually align and quantify expression of the genes for these substances in nuclei of the human hypothalamus. The hypothalamus was arbitrarily divided into rostral, intermediate, and caudal regions. The rostral region, containing the paraventricular nucleus (PVN), was defined by discrete localization of CRF- and AVP-expressing neurons, whereas distinct relationships between HDC, MCH, and ORX mRNA-expressing neurons delineated specific levels within the intermediate and caudal regions. Quantitative mRNA signal intensity measurements revealed no significant differences in overall CRF or AVP expression at any rostrocaudal level of the PVN. HDC mRNA expression was highest at the level of the premammillary area, which included the dorsomedial and tuberomammillary nuclei as well as the dorsolateral hypothalamic area. In addition, the overall intensity of hybridization signal exhibited by both MCH and ORX mRNA-expressing neurons peaked in distinct intermediate and caudal hypothalamic regions. These results suggest that human hypothalamic neurons involved in the regulation of the HPA axis display distinct neurochemical patterns that may encompass multiple local nuclei. J. Comp. Neurol. 518:4591–4611, 2010. © 2010 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78077/1/22480_ftp.pd

Neuropeptide and Small Transmitter Coexistence: Fundamental Studies and Relevance to Mental Illness

Neuropeptides are auxiliary messenger molecules that always co-exist in nerve cells with one or more small molecule (classic) neurotransmitters. Neuropeptides act both as transmitters and trophic factors, and play a role particularly when the nervous system is challenged, as by injury, pain or stress. Here neuropeptides and coexistence in mammals are reviewed, but with special focus on the 29/30 amino acid galanin and its three receptors GalR1, -R2 and -R3. In particular, galanin’s role as a co-transmitter in both rodent and human noradrenergic locus coeruleus (LC) neurons is addressed. Extensive experimental animal data strongly suggest a role for the galanin system in depression–like behavior. The translational potential of these results was tested by studying the galanin system in postmortem human brains, first in normal brains, and then in a comparison of five regions of brains obtained from depressed people who committed suicide, and from matched controls. The distribution of galanin and the four galanin system transcripts in the normal human brain was determined, and selective and parallel changes in levels of transcripts and DNA methylation for galanin and its three receptors were assessed in depressed patients who committed suicide: upregulation of transcripts, e.g., for galanin and GalR3 in LC, paralleled by a decrease in DNA methylation, suggesting involvement of epigenetic mechanisms. It is hypothesized that, when exposed to severe stress, the noradrenergic LC neurons fire in bursts and release galanin from their soma/dendrites. Galanin then acts on somato-dendritic, inhibitory galanin autoreceptors, opening potassium channels and inhibiting firing. The purpose of these autoreceptors is to act as a ‘brake’ to prevent overexcitation, a brake that is also part of resilience to stress that protects against depression. Depression then arises when the inhibition is too strong and long lasting – a maladaption, allostatic load, leading to depletion of NA levels in the forebrain. It is suggested that disinhibition by a galanin antagonist may have antidepressant activity by restoring forebrain NA levels. A role of galanin in depression is also supported by a recent candidate gene study, showing that variants in genes for galanin and its three receptors confer increased risk of depression and anxiety in people who experienced childhood adversity or recent negative life events. In summary, galanin, a neuropeptide coexisting in LC neurons, may participate in the mechanism underlying resilience against a serious and common disorder, MDD. Existing and further results may lead to an increased understanding of how this illness develops, which in turn could provide a basis for its treatment