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Hyeon Son,
Mounira Banasr,
Miyeon Choi,
Seung Yeon Chae,
Pawel Licznerski, Boyoung Lee,
Bhavya Voleti,
Nanxin Li,
Ashley Lepack,
Neil M Fournier,
Ka Rim Lee,
In Young Lee,
Juhyun Kim,
Joung-Hun Kim,
Yong Ho Kim,
Sung Jun Jung,
Ronald S Duman
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ABSTRACT: Decreased neuronal dendrite branching and plasticity of the hippocampus, a limbic structure implicated in mood disorders, is thought to contribute to the symptoms of depression. However, the mechanisms underlying this effect, as well as the actions of antidepressant treatment, remain poorly characterized. Here, we show that hippocampal expression of neuritin, an activity-dependent gene that regulates neuronal plasticity, is decreased by chronic unpredictable stress (CUS) and that antidepressant treatment reverses this effect. We also show that viral-mediated expression of neuritin in the hippocampus produces antidepressant actions and prevents the atrophy of dendrites and spines, as well as depressive and anxiety behaviors caused by CUS. Conversely, neuritin knockdown produces depressive-like behaviors, similar to CUS exposure. The ability of neuritin to increase neuroplasticity is confirmed in models of learning and memory. Our results reveal a unique action of neuritin in models of stress and depression, and demonstrate a role for neuroplasticity in antidepressant treatment response and related behaviors.
Proceedings of the National Academy of Sciences 06/2012; 109(28):11378-83. · 9.68 Impact Factor
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ABSTRACT: Vascular endothelial growth factor (VEGF) is a hypoxia-induced angiogenic protein that exhibits a broad range of neurotrophic and neuroprotective effects in the central nervous system. Given that neurogenesis occurs in close proximity to blood vessels, increasing evidence has suggested that VEGF may constitute an important link between neurogenesis and angiogenesis. Although it is known that VEGF can directly stimulate the proliferation of neuronal progenitors, the underlying signaling pathways responsible in this process are not fully understood. Thus, in the present study, we set out to examine the requirement of two downstream targets of the VEGF/Flk-1 signaling network, the phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) pathways, in producing the mitogenic effects of VEGF. Both in vivo and in vitro experiments showed that a single treatment of VEGF activated Erk1/2 and Akt signaling pathways in the adult rat hippocampus and in cultured hippocampal neuronal progenitor cells. This effect was blocked with the VEGF/Flk-1 inhibitor SU5416. Importantly, microinfusion of VEGF into the rat brain also induced pCREB expression in the dentate gyrus and increased the number of BrdU-labeled cells in the dentate subgranular zone. Double immunofluorescence labeling revealed that a large proportion of BrdU-labeled cells expressed activated forms of Flk-1, Erk1/2, and Akt. Interestingly, treatment with the SSRI fluoxetine, which is well known to stimulate neurogenesis and VEGF-signaling, also produced a similar expression pattern of Erk1/2 and Akt in proliferating cells. Finally, pharmacological experiments showed that administration of inhibitors of either MAPK/ERK (U0126) or PI3K (LY294002) blocked VEGF-stimulation of hippocampal cell proliferation in vivo and in vitro. Taken together, our findings demonstrate that the proliferative actions of VEGF require activation of both ERK and Akt signaling cascades and that these intracellular pathways are stimulated almost exclusively in actively proliferating neuronal progenitor cells of the adult hippocampus.
Neuropharmacology 05/2012; 63(4):642-52. · 4.81 Impact Factor
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ABSTRACT: Despite widely reported clinical and preclinical studies of rapid antidepressant actions of glutamate N-methyl-D-aspartate (NMDA) receptor antagonists, there has been very little work examining the effects of these drugs in stress models of depression that require chronic administration of antidepressants or the molecular mechanisms that could account for the rapid responses.
We used a rat 21-day chronic unpredictable stress (CUS) model to test the rapid actions of NMDA receptor antagonists on depressant-like behavior, neurochemistry, and spine density and synaptic function of prefrontal cortex neurons.
The results demonstrate that acute treatment with the noncompetitive NMDA channel blocker ketamine or the selective NMDA receptor 2B antagonist Ro 25-6981 rapidly ameliorates CUS-induced anhedonic and anxiogenic behaviors. We also found that CUS exposure decreases the expression levels of synaptic proteins and spine number and the frequency/amplitude of synaptic currents (excitatory postsynaptic currents) in layer V pyramidal neurons in the prefrontal cortex and that these deficits are rapidly reversed by ketamine. Blockade of the mammalian target of rapamycin protein synthesis cascade abolishes both the behavioral and biochemical effects of ketamine.
The results indicate that the structural and functional deficits resulting from long-term stress exposure, which could contribute to the pathophysiology of depression, are rapidly reversed by NMDA receptor antagonists in a mammalian target of rapamycin dependent manner.
Biological psychiatry 02/2011; 69(8):754-61. · 8.93 Impact Factor
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ABSTRACT: The rapid antidepressant response after ketamine administration in treatment-resistant depressed patients suggests a possible new approach for treating mood disorders compared to the weeks or months required for standard medications. However, the mechanisms underlying this action of ketamine [a glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonist] have not been identified. We observed that ketamine rapidly activated the mammalian target of rapamycin (mTOR) pathway, leading to increased synaptic signaling proteins and increased number and function of new spine synapses in the prefrontal cortex of rats. Moreover, blockade of mTOR signaling completely blocked ketamine induction of synaptogenesis and behavioral responses in models of depression. Our results demonstrate that these effects of ketamine are opposite to the synaptic deficits that result from exposure to stress and could contribute to the fast antidepressant actions of ketamine.
Science 08/2010; 329(5994):959-64. · 31.20 Impact Factor
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ABSTRACT: This study extends earlier work on the role of vascular endothelial growth factor (VEGF) in the actions of antidepressant treatment in two key areas. First, by determining the requirement for VEGF in the actions of a 5-HT selective reuptake inhibitor (SSRI), fluoxetine in behavioral models of depression/antidepressant response; and second, by examining the role of the 5-HT1A receptor subtype in the regulation of VEGF, and the cellular localization of antidepressant regulation of VEGF expression. The results show that pharmacological inhibition of VEGF receptor signaling blocks the behavioral actions of fluoxetine in rats subjected to chronic unpredictable stress. Infusions of SU5416 or SU1498, two structurally dissimilar inhibitors of VEGF-Flk-1 receptor signaling, block the antidepressant effects of fluoxetine on sucrose preference, immobility in the forced swim test, and latency to feed in the novelty suppressed feeding paradigm. We also show that activation of 5-HT1A receptors is sufficient to induce VEGF expression and that a 5-HT1A antagonist blocks both the increase in VEGF and behavioral effects induced by fluoxetine. Finally, double labeling studies show that chronic fluoxetine administration increases VEGF expression in both neurons and endothelial cells in the hippocampus. Taken together these studies show that VEGF is necessary for the behavioral effects of the SSRI fluoxetine, as well as norepinephrine selective reuptake inhibitor, and that these effects may be mediated by 5-HT1A receptors located on neurons and endothelial cells.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2009; 34(11):2459-68. · 6.99 Impact Factor
