Regulation of Activin mRNA and Smad2 Phosphorylation by Antidepressant Treatment in the Rat Brain: Effects in Behavioral Models

Dow, Antonia; Russell, David; Duman, Ronald S.

doi:10.1523/jneurosci.5155-04.2005

Cited by 77 publications

(78 citation statements)

References 44 publications

(61 reference statements)

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“…Enhancement of TGF-β signaling by activin, a member of TGF-β superfamily, promotes an antide-pressantlike effect (74). In the present study, SMAD4 expression is decreased by HSP-H, suggesting that the behavioral changes in the postpartum model could be precipitated by attenuated TGF-β signaling.…”

Section: Gene Expression Analysissupporting

confidence: 48%

A Postpartum Model in Rat: Behavioral and Gene Expression Changes Induced by Ovarian Steroid Deprivation

Suda

Segi-Nishida

Newton

et al. 2008

Biological Psychiatry

136

103

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Background-Postpartum depression (PPD) affects approximately 10% to 20% of women during the first 4 weeks of the postpartum period and is characterized by labile mood with prominent anxiety and irritability, insomnia,and depressive mood. During the postpartum period, elevated ovarian hormones abruptly decrease to the early follicular phase levels that are postulated to play a major role in triggering PPD. However, the underlying neurobiological mechanisms that contribute to PPD have not been determined.

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Section: Gene Expression Analysissupporting

confidence: 48%

A Postpartum Model in Rat: Behavioral and Gene Expression Changes Induced by Ovarian Steroid Deprivation

Suda

Segi-Nishida

Newton

et al. 2008

Biological Psychiatry

136

103

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“…Embryonic neurons are dependent on the continual presence of growth factors for their survival while adult neurons may require trophic support only in times of injury (Benn and Woolf, 2004). Activin mRNA and protein are present at basal levels throughout the adult brain including cortical regions (Roberts et al, 1996) with significant upregulation of activin mRNA, its protein and activin signals in adult neurons can be detected within hours after injury (our data; Tretter et al, 1996;Dow et al, 2005;Bottner et al, 2006). Because activin administration protects adult hippocampal neurons from excitotoxic kainic acid and quinolic acid addition in vivo Tretter et al, 2000), it seems likely that increased amounts will improve neuronal survival after ischemic injury.…”

Section: Discussionmentioning

confidence: 64%

“…Variations in neural responsiveness to activin may be because of differences in receptor expression (Cameron et al, 1994;Funaba et al, 1997) or intracellular mechanisms activated by activin in neuronal phenotypes. One recent report suggests that activin mRNA and signaling, as well as behavioral improvements are also noted after antidepressant activity (Dow et al, 2005), but the mechanism of action in this case is not known. It Figure 6 mRNA changes after hypoxic exposure.…”

Section: Discussionmentioning

confidence: 82%

Activin is a Neuronal Survival Factor that is Rapidly Increased after Transient Cerebral Ischemia and Hypoxia in Mice

Mukerji

Katsman

Wilber

et al. 2006

J Cereb Blood Flow Metab

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One approach for developing targeted stroke therapies is to identify the neuronal protective and destructive signaling pathways and gene expression that follow ischemic insult. In some neural injury models, the transforming growth factor-beta family member activin can provide neuroprotective effects in vivo and promote neuronal survival. This study tests if activin supports cortical neurons after ischemic challenge in vitro and if signals after cerebral ischemia involve activin in vivo. In a defined cell culture model that uses hydrogen peroxide (H2O2)-free radical stress, activin addition maintained neuronal survival. H2O2 treatment increased activin mRNA twofold in surviving cortical neurons, and inhibition of activin with neutralizing antibodies caused neuronal death. These data identify activin gene changes as a rapid response to oxidative stress, and indicate that endogenous activin acts as a protective factor for cortical neurons in vitro. Similarly, after transient focal cerebral ischemia in adult mice, activin mRNA increased at 1 and 4 h ipsilateral to the infarct but returned to control values at 24 h after reperfusion. Intracellular activated smad signals were detected in neurons adjacent to the infarct. Activin was also increased after 2 h of 11% hypoxia. Activin mRNA increased at 1 h but not 4 or 24 h after hypoxia, similar to the time course of erythropoietin and vascular endothelial growth factor induction. These findings identify activin as an early-regulated gene response to transient ischemia and hypoxia, and its function in cortical neuron survival during oxidative challenge provides a basis to test activin as a potential therapeutic in stroke injury.

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“…Although we report here that genetic disruption of activin signaling decreased anxiety-related behavior, a recent study showed that hippocampal infusion of activin exerted antidepressant-like activity in the forced swimming test. 56 Although caution is warranted when inferring abnormal emotional processing from altered behavior in animal tasks, it is tempting to speculate that, by tuning GABAergic neurotransmission, activin is essential to provide the optimal balance between anxiety and depression. In this scenario, activin signaling would adjust the level of anxiety to avert the daredevil behavior of dnActRIB mice, while, at the same time, preventing the behavioral immobility associated with depression.…”

Section: Discussionmentioning

confidence: 99%

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Zheng

Adelsberger²,

et al. 2008

Mol Psychiatry

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Activin, a member of the transforming growth factor-b superfamily, affords neuroprotection in acute brain injury, but its physiological functions in normal adult brain are largely unknown. Using transgenic (tg) mice expressing a dominant-negative activin receptor mutant under the control of the CaMKIIa promoter in forebrain neurons, we identified activin as a key regulator of c-aminobutyric acid (GABA)ergic synapses and anxiety-like behavior. In the open field, wildtype (wt) and tg mice did not differ in spontaneous locomotion and exploration behavior. However, tg mice visited inner fields significantly more often than wt mice. In the light-dark exploration test, tg mice made more exits, spent significantly more time on a well-lit elevated bar and went farther away from the dark box as compared to wt mice. In addition, the anxiolytic effect of diazepam was abrogated in tg mice. Thus the disruption of activin receptor signaling produced a low-anxiety phenotype that failed to respond to benzodiazepines. In whole-cell recordings from hippocampal pyramidal cells, enhanced spontaneous GABA release, increased GABA tonus, reduced benzodiazepine sensitivity and augmented GABA B receptor function emerged as likely substrates of the low-anxiety phenotype. These data provide strong evidence that activin influences pre-and postsynaptic components of GABAergic synapses in a highly synergistic fashion. Given the crucial role of GABAergic neurotransmission in emotional states, anxiety and depression, dysfunctions of activin receptor signaling could be involved in affective disorders: and drugs affecting this pathway might show promise for psychopharmacological treatment.

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Regulation of Activin mRNA and Smad2 Phosphorylation by Antidepressant Treatment in the Rat Brain: Effects in Behavioral Models

Abstract: Activin is a member of the transforming growth factor-␤ family that is involved in cell differentiation

Cited by 77 publications

References 44 publications

A Postpartum Model in Rat: Behavioral and Gene Expression Changes Induced by Ovarian Steroid Deprivation

A Postpartum Model in Rat: Behavioral and Gene Expression Changes Induced by Ovarian Steroid Deprivation

Activin is a Neuronal Survival Factor that is Rapidly Increased after Transient Cerebral Ischemia and Hypoxia in Mice

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

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