Region-specific transcriptional changes following the three antidepressant treatments electro convulsive therapy, sleep deprivation and fluoxetine

Abstract

The significant proportion of depressed patients that are resistant to monoaminergic drug therapy and the slow onset of therapeutic effects of the selective serotonin reuptake inhibitors (SSRIs)/serotonin/noradrenaline reuptake inhibitors (SNRIs) are two major reasons for the sustained search for new antidepressants. In an attempt to identify common underlying mechanisms for fast-and slow-acting antidepressant modalities, we have examined the transcriptional changes in seven different brain regions of the rat brain induced by three clinically effective antidepressant treatments: electro convulsive therapy (ECT), sleep deprivation (SD), and fluoxetine (FLX), the most commonly used slow-onset antidepressant. Each of these antidepressant treatments was applied with the same regimen known to have clinical efficacy: 2 days of ECT (four sessions per day), 24 h of SD, and 14 days of daily treatment of FLX, respectively. Transcriptional changes were evaluated on RNA extracted from seven different brain regions using the Affymetrix rat genome microarray 230 2.0. The gene chip data were validated using in situ hybridization or autoradiography for selected genes. The major findings of the study are:1. The transcriptional changes induced by SD, ECT and SSRI display a regionally specific distribution distinct to each treatment. 2. The fast-onset, short-lived antidepressant treatments ECT and SD evoked transcriptional changes primarily in the catecholaminergic system, whereas the slow-onset antidepressant FLX treatment evoked transcriptional changes in the serotonergic system. 3. ECT and SD affect in a similar manner the same brain regions, primarily the locus coeruleus, whereas the effects of FLX were primarily in the dorsal raphe and hypothalamus, suggesting that both different regions and pathways account for fast onset but short lasting effects as compared to slow-onset but long-lasting effects. However, the similarity between effects of ECT and SD is somewhat confounded by the fact that the two treatments appear to regulate a number of transcripts in an opposite manner. 4. Multiple transcripts (e.g. brain-derived neurotrophic factor (BDNF), serum/glucocorticoidregulated kinase (Sgk1)), whose level was reported to be affected by antidepressants or behavioral manipulations, were also found to be regulated by the treatments used in the present study. Several novel findings of transcriptional regulation upon one, two or all three treatments were made, for the latter we highlight homer, erg2, HSP27, the proto oncogene ret, sulfotransferase family 1A (Sult1a1), glycerol 3-phosphate dehydrogenase (GPD3), the orphan receptor G protein-coupled receptor 88 (GPR88) and a large number of expressed sequence tags (ESTs). 5. Transcripts encoding proteins involved in synaptic plasticity in the hippocampus were strongly affected by ECT and SD, but not by FLX.The novel transcripts, concomitantly regulated by several antidepressant treatments, may represent novel targets for fast onset, long-duration antidepressants.

Astrocytes are a neural target of morphine action via glucocorticoid receptor‐dependent signaling

“…This gene was at the top of the list of genes regulated, both, by dexamethasone in cultured astrocytes and by morphine in the mouse striatum. Alterations in the level of Sgk1 transcript or protein have been previously observed in the CNS in various models of stress (Koya et al, 2005;Murata et al, 2005;Yuen et al, 2010), after exposure to dexamethasone (Sato et al, 2008;David et al, 2005;van Gemert et al, 2006), drugs of abuse (Piechota et al, 2010b) and antidepressants (Conti et al, 2007), as well as in animal models of memory formation (von Hertzen and Giese, 2005) and neurodegeneration (Iwata et al, 2004;Rangone et al, 2004;Schoenebeck et al, 2005). Our results show that GR-responsive isoforms of Sgk1 are confined to astrocytes.…”

The impact of sleep loss on hippocampal function

“…These widespread changes in hippocampal gene expression were reversed with 2.5 h of recovery sleep following sleep deprivation . Longer periods of sleep deprivation have also been examined with regard to gene expression in the hippocampus using microarray analysis to explore the relationship between age, stress, depression, and sleep disruption (Conti et al 2007;Porter et al 2012). In these studies, selective changes in genes related to presynaptic machinery and synaptic plasticity were identified.…”

Effects of Sleep and Wake on Oligodendrocytes and Their Precursors

“…The TRAP methodology involves cell-specific expression of an eGFP-L10a ribosomal transgene to tag polysomes and immunoaffinity purify mRNAs. Thus, in addition to targeting specific cell groups, this method isolates mRNAs attached to ribosomes, providing an almost "translational" view of cellular function (Doyle et al, 2008). We find that the expression of hundreds of transcripts translated in oligodendrocytes changes because of sleep and wake, and many wake-related and sleep-related genes have complementary or opposite functions.…”