Requirement of Hippocampal Neurogenesis for the Behavioral Effects of Antidepressants

Santarelli, Luca; Saxe, Michael; Gross, Cornelius; Surget, Alexandre; Battaglia, Fortunato; Dulawa, Stephanie C.; Weisstaub, Noelia V.; Lee, James; Duman, Ronald S.; Arancio, Ottavio; Belzung, Catherine; Hen, René

doi:10.1126/science.1083328

Cited by 3,911 publications

(3,534 citation statements)

References 33 publications

Supporting

153

Mentioning

3,288

Contrasting

Unclassified

Order By: Relevance

“…This suggest that increases in hippocampal volume observed after long‐term antidepressant treatment are likely mediated through the activation of neurogenic pathways, as opposed to solely a reduction in neuronal cell death. However, our AHN gene set was not enriched for genes predictive of antidepressant response, suggesting that in contrast to non‐human animal findings (Santarelli et al, 2003), AHN may not be the cellular mechanism governing therapeutic response to SSRIs in humans. There are, however, a number of alternative interpretations to this finding.…”

Section: Discussioncontrasting

confidence: 59%

“…However, due to the inaccessible nature of hippocampal progenitor cells in patients, there has been no conclusive evidence directly supporting this relationship in humans. Furthermore, based on convincing non‐human animal data, AHN has been implicated as a cellular mechanism governing antidepressant action (Santarelli et al, 2003) but this, to our knowledge, has yet to be demonstrated in humans.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The genome‐wide expression effects of escitalopram and its relationship to neurogenesis, hippocampal volume, and antidepressant response

Powell

Murphy

Jong

et al. 2017

American J of Med Genetics Pt B

View full text Add to dashboard Cite

Antidepressant‐induced hippocampal neurogenesis (AHN) is hypothesized to contribute to increases in hippocampal volume among major depressive disorder patients after long‐term treatment. Furthermore, rodent studies suggest AHN may be the cellular mechanism mediating the therapeutic benefits of antidepressants. Here, we perform the first investigation of genome‐wide expression changes associated with AHN in human cells. We identify gene expression networks significantly activated during AHN, and we perform gene set analyses to probe the molecular relationship between AHN, hippocampal volume, and antidepressant response. The latter were achieved using genome‐wide association summary data collected from 30,717 individuals as part of the ENIGMA Consortium (genetic predictors of hippocampal volume dataset), and data collected from 1,222 major depressed patients as part of the NEWMEDS Project (genetic predictors of response to antidepressants dataset). Our results showed that the selective serotonin reuptake inhibitor, escitalopram evoked AHN in human cells; dose‐dependently increasing the differentiation of cells into neuroblasts, as well as increasing gliogenesis. Activated genome‐wide expression networks relate to axon and microtubule formation, and ribosomal biogenesis. Gene set analysis revealed that gene expression changes associated with AHN were nominally enriched for genes predictive of hippocampal volume, but not for genes predictive of therapeutic response.

show abstract

Section: Discussioncontrasting

confidence: 59%

Section: Introductionmentioning

confidence: 99%

The genome‐wide expression effects of escitalopram and its relationship to neurogenesis, hippocampal volume, and antidepressant response

Powell

Murphy

Jong

et al. 2017

American J of Med Genetics Pt B

View full text Add to dashboard Cite

show abstract

“…This supports recent findings indicating an important role of the hippocampus in depression and in the antidepressant response to pharmacotherapy. 52,53 Also, altered size and impaired function of the hippocampus have been found in a number of recent clinical imaging studies of major depression (for a meta-analysis see Campbell 54 ). Furthermore, expression changes in genes implicated in the second messenger systems, such as kinases, phosphatases and the adenylate cyclase 8 gene (ADCY8) were observed in the hippocampus, supporting previous evidence of synaptic plasticity alterations in mood disorders 55,56 and in antidepressant response beyond the neurotransmitter and receptor level.…”

Section: Discussionmentioning

confidence: 99%

Patterns of gene expression in the limbic system of suicides with and without major depression

et al. 2007

View full text Add to dashboard Cite

The limbic system has consistently been associated with the control of emotions and with mood disorders. The goal of this study was to identify new molecular targets associated with suicide and with major depression using oligonucleotide microarrays in the limbic system (amygdala, hippocampus, anterior cingulate gryus (BA24) and posterior cingulate gyrus (BA29)). A total of 39 subjects were included in this study. They were all male subjects and comprised 26 suicides (depressed suicides = 18, non depressed suicides = 8) and 13 matched controls. Brain gene expression analysis was carried out on human brain samples using the Affymetrix HG U133 chip set. Differential expression in each of the limbic regions showed group-specific patterns of expression, supporting particular neurobiological mechanisms implicated in suicide and depression. Confirmation of genes selected based on their significance and the interest of their function with reverse transcriptase-polymerase chain reaction showed consistently correlated signals with the results obtained in the microarray analysis. Gene ontology analysis with differentially expressed genes revealed an overrepresentation of transcription and metabolism-related genes in the hippocampus and amygdala, whereas differentially expressed genes in BA24 and BA29 were more generally related to RNA-binding, regulation of enzymatic activity and protein metabolism. Limbic expression patterns were most extensively altered in the hippocampus, where processes related to major depression were associated with altered expression of factors involved with transcription and cellular metabolism. Additionally, our results confirm previous evidence pointing to global alteration of gabaergic neurotransmission in suicide and major depression, offering new avenues in the study and possibly treatment of such complex disorders. Overall, these data suggest that specific patterns of expression in the limbic system contribute to the etiology of depression and suicidal behaviors and highlight the role of the hippocampus in major depression.

show abstract

“…In addition, robalzotan is an effective antagonist of postsynaptic 5-HT 1A receptors in laboratory animals and in humans (Johansson et al, 1997;Andree et al, 2003). Such receptors are believed to play an important role in the antidepressant response of serotonergic agents (Blier and Ward, 2003;Santarelli et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Electrophysiological Evidence for the Tonic Activation of 5-HT1A Autoreceptors in the Rat Dorsal Raphe Nucleus

Haddjeri

Lavoie

Blier

2004

Neuropsychopharmacol

View full text Add to dashboard Cite

Serotonin (5-hydroxytryptamine, 5-HT) and norepinephine (NE) neurons have reciprocal connections. These may thus interfere with anticipated effects of selective pharmacological agents targeting these neurons. The main goal of the present study was to assess whether the somatodendritic 5-HT 1A autoreceptor is tonically activated by endogenous 5-HT in anesthetised rats, using in vivo extracellular unitary recordings. In rats with their NE neurons lesioned using 6-hydroxydopamine (6-OHDA) and in controls administered the NE reuptake inhibitor desipramine to suppress NE neuronal firing, the a 2 -adrenoceptor agonist clonidine no longer inhibited 5-HT neuron firing, therefore indicating the important modulation of the firing activity of 5-HT neurons by NE neurons. In control rats, the administration of the potent and selective 5-HT 1A receptor antagonist WAY 100,635 ((N-{2-[4(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)cyclohexanecarboxamide trihydroxychloride) (100 mg/kg, i.v.) did not modify the spontaneous firing activity of 5-HT neurons, but in NE-lesioned rats using either 6-OHDA or DSP-4, WAY 100,635 produced a mean firing increase of 80 and 69%, respectively. When desipramine and D-amphetamine were used in control rats to prevent alterations in the availability of NE in the dorsal raphe, again WAY 100,635 produced a significant disinhibition of the firing of 5-HT neurons (83 and 53%, respectively). These data support the notion that the NE system tonically activates the firing activity of 5-HT neurons. When the fluctuations of the function of NE neurons normally produced by WAY 100,635 were prevented, a tonic activation of 5-HT 1A autoreceptors by endogenous 5-HT was unmasked.

show abstract

Requirement of Hippocampal Neurogenesis for the Behavioral Effects of Antidepressants

Cited by 3,911 publications

References 33 publications

The genome‐wide expression effects of escitalopram and its relationship to neurogenesis, hippocampal volume, and antidepressant response

The genome‐wide expression effects of escitalopram and its relationship to neurogenesis, hippocampal volume, and antidepressant response

Patterns of gene expression in the limbic system of suicides with and without major depression

Electrophysiological Evidence for the Tonic Activation of 5-HT1A Autoreceptors in the Rat Dorsal Raphe Nucleus

Contact Info

Product

Resources

About