scholarly journals Ketamine Induces Lasting Antidepressant Effects by Modulating the NMDAR/CaMKII-Mediated Synaptic Plasticity of the Hippocampal Dentate Gyrus in Depressive Stroke Model

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Idriss Ali Abdoulaye ◽  
Shan-shan Wu ◽  
Enkhmurun Chibaatar ◽  
Da-fan Yu ◽  
Kai Le ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Dentate Gyrus ◽  
Brain Regions ◽  
Artery Occlusion ◽  
Mild Stress ◽  
Sprague Dawley ◽  
Poststroke Depression ◽  
Hippocampal Dentate Gyrus ◽  
Downstream Signaling ◽  
Antidepressant Effects

Background. Ketamine has been shown to possess lasting antidepressant properties. However, studies of the mechanisms involved in its effects on poststroke depression are nonexistent. Methods. To investigate these mechanisms, Sprague-Dawley rats were treated with a single local dose of ketamine after middle cerebral artery occlusion and chronic unpredicted mild stress. The effects on the hippocampal dentate gyrus were analyzed through assessment of the N-methyl-D-aspartate receptor/calcium/calmodulin-dependent protein kinase II (NMDAR/CaMKII) pathway, synaptic plasticity, and behavioral tests. Results. Ketamine administration rapidly exerted significant and lasting improvements of depressive symptoms. The biochemical analysis showed rapid, selective upregulation and downregulation of the NMDAR2-β and NMDAR2-α subtypes as well as their downstream signaling proteins β-CaMKII and α-phosphorylation in the dentate gyrus, respectively. Furthermore, the colocalization analysis indicated a significant and selectively increased conjunction of β-CaMKII and postsynaptic density protein 95 (PSD95) coupled with a notable decrease in NMDAR2-β association with PSD95 after ketamine treatment. These changes translated into significant and extended synaptic plasticity in the dentate gyrus. Conclusions. These findings not only suggest that ketamine represents a viable candidate for the treatment of poststroke depression but also that ketamine’s lasting antidepressant effects might be achieved through modulation of NMDAR/CaMKII-induced synaptic plasticity in key brain regions.

scholarly journals Chronic Unexpected Mild Stress Destroys Synaptic Plasticity of Neurons through a Glutamate Transporter, GLT-1, of Astrocytes in the Ischemic Stroke Rat

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Dafan Yu ◽  
Zhenxing Cheng ◽  
Abdoulaye Idriss Ali ◽  
Jiamin Wang ◽  
Kai Le ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Synaptic Plasticity ◽  
Dentate Gyrus ◽  
Average Distance ◽  
Glutamate Transporter ◽  
Synaptic Cleft ◽  
Mild Stress ◽  
Poststroke Depression ◽  
Transmission Electron ◽  
Synaptic Formation

Background and Objective. Chronic unexpected mild stress (CUMS) destroys synaptic plasticity of hippocampal regenerated neurons that may be involved in the occurrence of poststroke depression. Astrocytes uptake glutamate at the synapse and provide metabolic support for neighboring neurons. Currently, we aim to investigate whether CUMS inhibits synaptic formation of regenerated neurons through a glutamate transporter, GLT-1, of astrocytes in the ischemic stroke rats. Method. We exposed the ischemic stroke rats to ceftriaxone, during the CUMS intervention period to determine the effects of GLT-1 on glutamate circulation by immunofluorescence and mass spectrometry and its influences to synaptic plasticity by western blot and transmission electron microscopy. Result. CUMS evidently reduced the level of astroglial GLT-1 in the hippocampus of the ischemic rats (p<0.05), resulting in smaller amount of glutamate being transported into astrocytes surrounding synapses (p<0.05), and then expression of synaptophysin was suppressed (p<0.05) in hippocampal dentate gyrus. The ultrastructures of synapses in dentate gyrus were adversely influenced including decreased proportion of smile synapses, shortened thickness of postsynaptic density, reduced number of vesicles, and widened average distance of the synaptic cleft (all p<0.05). Moreover, ceftriaxone can promote glutamate circulation and synaptic plasticity (all p<0.05) by raising astroglial GLT-1 (p<0.05) and then improve depressive behaviors of the CUMS-induced model rats (p<0.05). Conclusion. Our study shows that CUMS destroys synaptic plasticity of regenerated neurons in the hippocampus through a glutamate transporter, GLT-1, of astrocytes in the ischemic stroke rats. This may indicate one potential pathogenesis of poststroke depression.

scholarly journals Postischemic Anhedonia Associated with Neurodegenerative Changes in the Hippocampal Dentate Gyrus of Rats

2016 ◽  
Vol 2016 ◽  
pp. 1-20
Author(s):  
Jiro Kasahara ◽  
Hiroto Uchida ◽  
Kenta Tezuka ◽  
Nanae Oka
Keyword(s):  
Dentate Gyrus ◽  
Neuronal Loss ◽  
Immunohistochemical Analysis ◽  
Granular Cell ◽  
Artery Occlusion ◽  
Poststroke Depression ◽  
Hippocampal Dentate Gyrus ◽  
Antidepressant Imipramine ◽  
Effective Use ◽  
Cerebral Artery Occlusion

Poststroke depression is one of the major symptoms observed in the chronic stage of brain stroke such as cerebral ischemia. Its pathophysiological mechanisms, however, are not well understood. Using the transient right middle cerebral artery occlusion- (MCAO-, 90 min) operated rats as an ischemia model in this study, we first observed that aggravation of anhedonia spontaneously occurred especially after 20 weeks of MCAO, and it was prevented by chronic antidepressants treatment (imipramine or fluvoxamine). The anhedonia specifically associated with loss of the granular neurons in the ipsilateral side of hippocampal dentate gyrus and was also prevented by an antidepressant imipramine. Immunohistochemical analysis showed increased apoptosis inside the granular cell layer prior to and associated with the neuronal loss, and imipramine seemed to recover the survival signal rather than suppressing the death signal to prevent neurons from apoptosis. Proliferation and development of the neural stem cells were increased transiently in the subgranular zone of both ipsi- and contralateral hippocampus within one week after MCAO and then decreased and almost ceased after 6 weeks of MCAO, while chronic imipramine treatment prevented them partially. Overall, our study suggests new insights for the mechanistic correlation between poststroke depression and the delayed neurodegenerative changes in the hippocampal dentate gyrus with effective use of antidepressants on them.

scholarly journals S-Ketamine Exerts Antidepressant Effects by Regulating Rac1 Gtpase Mediated Synaptic Plasticity in the Hippocampus of Stressed Rats

2021 ◽  
Author(s):  
Xianlin Zhu ◽  
Fan Zhang ◽  
Yufeng You ◽  
Hongbai Wang ◽  
Su Yuan ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Molecular Mechanisms ◽  
Electrophysiological Study ◽  
Transmission Function ◽  
Long Term Potentiation ◽  
Neuronal Morphology ◽  
Antidepressant Effect ◽  
Mild Stress ◽  
Antidepressant Effects ◽  
Expression And Activity

Abstract Clinical studies have found that ketamine has a rapid and lasting antidepressant effect, especially in the case of patients with major depressive disorder (MDD). The molecular mechanisms, however, remain unclear. In this study, we observe the effects of S-Ketamine on the expression of Rac1, neuronal morphology, and synaptic transmission function in the hippocampus of stressed rats. Chronic unpredictable mild stress (CUMS) was used to construct stressed rats. The rats were given a different regimen of ketamine (20mg/kg, i.p.) and Rac1 inhibitor NSC23766 (50µg, ICV) treatment. The depression-like behavior of rats was evaluated by sucrose preference test and open-field test. The protein expression of Rac1, Glur1, synapsin1, and PSD95 in the hippocampus was detected by Western blot. Pull-down analysis was used to examine the activity of Rac1. Golgi staining and electrophysiological study were used to observe the neuronal morphology and long-term potentiation (LTP). Our results showed that ketamine can up-regulate the expression and activity of Rac1; increase the spine density and the expression of synaptic-related proteins such as Glur1, Synapsin1, and PSD95 in the hippocampus of stressed rats; reduce the CUMS-induced LTP impairments; and consequently improve depression-like behavior. However, Rac1 inhibitor NSC23766 could have effectively reversed ketamine-mediated changes in the hippocampus of rats and counteracted its antidepressant effects. The specific mechanism of S-ketamine's antidepressant effect may be related to the up-regulation of the expression and activity of Rac1 in the hippocampus of stressed rats, thus enhancing synaptic plasticity.

scholarly journals Long-term potentiation expands information content of hippocampal dentate gyrus synapses

2018 ◽  
Vol 115 (10) ◽  
pp. E2410-E2418 ◽  
Author(s):  
Cailey Bromer ◽  
Thomas M. Bartol ◽  
Jared B. Bowden ◽  
Dusten D. Hubbard ◽  
Dakota C. Hanka ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Dentate Gyrus ◽  
Storage Capacity ◽  
Unit Length ◽  
Long Term Potentiation ◽  
Information Storage ◽  
Perforant Path ◽  
Hippocampal Dentate Gyrus ◽  
Term Potentiation

An approach combining signal detection theory and precise 3D reconstructions from serial section electron microscopy (3DEM) was used to investigate synaptic plasticity and information storage capacity at medial perforant path synapses in adult hippocampal dentate gyrus in vivo. Induction of long-term potentiation (LTP) markedly increased the frequencies of both small and large spines measured 30 minutes later. This bidirectional expansion resulted in heterosynaptic counterbalancing of total synaptic area per unit length of granule cell dendrite. Control hemispheres exhibited 6.5 distinct spine sizes for 2.7 bits of storage capacity while LTP resulted in 12.9 distinct spine sizes (3.7 bits). In contrast, control hippocampal CA1 synapses exhibited 4.7 bits with much greater synaptic precision than either control or potentiated dentate gyrus synapses. Thus, synaptic plasticity altered total capacity, yet hippocampal subregions differed dramatically in their synaptic information storage capacity, reflecting their diverse functions and activation histories.

scholarly journals Xingnao Jieyu Decoction Ameliorates Poststroke Depression through the BDNF/ERK/CREB Pathway in Rats

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Tao Li ◽  
Dou Wang ◽  
Bingbing Zhao ◽  
Yongmei Yan
Keyword(s):  
Hippocampal Neurons ◽  
Artery Occlusion ◽  
Immunofluorescence Assay ◽  
Antidepressant Effect ◽  
Tunel Staining ◽  
Mild Stress ◽  
Poststroke Depression ◽  
Protein Levels ◽  
Swimming Test ◽  
Cerebral Artery Occlusion

Background.The neurotrophic pathway regulated by the brain-derived neurotrophic factor (BDNF) plays a crucial role in the pathogenesis of poststroke depression (PSD). How the traditional Chinese medicine compound preparation Xingnao Jieyu (XNJY) decoction regulates the neurotrophic pathway to treat PSD is unclear.Objective.This study aimed to investigate the antidepressant effect of XNJY decoction on a rat model of PSD and the molecular mechanism intervening in the neurotrophic pathway.Methods.After a middle cerebral artery occlusion model was established, chronic unpredictable mild stress was applied for 21 days to prepare a PSD model. XNJY groups and a fluoxetine (Flu) group of rats were intragastrically administered with XNJY and Flu, respectively, for 21 consecutive days. Depressive-like behaviors, including sucrose preference, open field test, and forced swimming test, were assessed. The survival and apoptosis of cortical and hippocampal neurons were evaluated by immunofluorescence assay and TUNEL staining. The contents of serotonin (5-HT), norepinephrine (NE), and BDNF in the cortex and hippocampus were determined by ELISA. The protein levels of BDNF, p-ERK/ERK, and p-CREB/CREB in the cortical and hippocampal regions were tested by Western blot.Results.The depressive-like behaviors markedly improved after XNJY and Flu treatment. XNJY and Flu promoted neuronal survival and protected cortical and hippocampal neurons from apoptosis. XNJY also increased the contents of 5-HT, NE, and BDNF and recovered the protein levels of p-ERK/ERK, p-CREB/CREB, and BDNF in the cortical and hippocampal regions.Conclusion.These results indicated that the XNJY decoction exerts an obvious antidepressant effect, which may be due to the regulation of the BDNF/ERK/CREB signaling pathway.

scholarly journals The Impacts of Swimming Exercise on Hippocampal Expression of Neurotrophic Factors in Rats Exposed to Chronic Unpredictable Mild Stress

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Pei Jiang ◽  
Rui-Li Dang ◽  
Huan-De Li ◽  
Li-Hong Zhang ◽  
Wen-Ye Zhu ◽  
...  
Keyword(s):  
Neurotrophic Factors ◽  
Vascular Function ◽  
Mrna Level ◽  
Brain Regions ◽  
Swimming Exercise ◽  
Mild Stress ◽  
Chronic Unpredictable Mild Stress ◽  
Major Function ◽  
Functional Changes ◽  
Antidepressant Effects

Depression is associated with stress-induced neural atrophy in limbic brain regions, whereas exercise has antidepressant effects as well as increasing hippocampal synaptic plasticity by strengthening neurogenesis, metabolism, and vascular function. A key mechanism mediating these broad benefits of exercise on the brain is induction of neurotrophic factors, which instruct downstream structural and functional changes. To systematically evaluate the potential neurotrophic factors that were involved in the antidepressive effects of exercise, in this study, we assessed the effects of swimming exercise on hippocampal mRNA expression of several classes of the growth factors (BDNF, GDNF, NGF, NT-3, FGF2, VEGF, and IGF-1) and peptides (VGF and NPY) in rats exposed to chronic unpredictable mild stress (CUMS). Our study demonstrated that the swimming training paradigm significantly induced the expression of BDNF and BDNF-regulated peptides (VGF and NPY) and restored their stress-induced downregulation. Additionally, the exercise protocol also increased the antiapoptotic Bcl-xl expression and normalized the CUMS mediated induction of proapoptotic Bax mRNA level. Overall, our data suggest that swimming exercise has antidepressant effects, increasing the resistance to the neural damage caused by CUMS, and both BDNF and its downstream neurotrophic peptides may exert a major function in the exercise related adaptive processes to CUMS.

scholarly journals Pathophysiology of depression and innovative treatments: remodeling glutamatergic synaptic connections

2014 ◽  
Vol 16 (1) ◽  
pp. 11-27 ◽  
Keyword(s):  
Receptor Antagonist ◽  
Synapse Formation ◽  
Brain Regions ◽  
Nmda Receptor Antagonist ◽  
Synaptic Connections ◽  
Downstream Signaling ◽  
Antidepressant Effects ◽  
Glutamate Transmission ◽  
And Function ◽  
New Generation

Despite the complexity and heterogeneity of mood disorders, basic and clinical research studies have begun to elucidate the pathophysiology of depression and to identify rapid, efficacious antidepressant agents. Stress and depression are associated with neuronal atrophy, characterized by loss of synaptic connections in key cortical and limbic brain regions implicated in depression. This is thought to occur in part via decreased expression and function of growth factors, such as brain-derived neurotrophic factor (BDNF), in the prefrontal cortex (PFC) and hippocampus. These structural alterations are difficult to reverse with typical antidepressants. However, recent studies demonstrate that ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist that produces rapid antidepressant actions in treatment-resistant depressed patients, rapidly increases spine synapses in the PFC and reverses the deficits caused by chronic stress. This is thought to occur by disinhibition of glutamate transmission, resulting in a rapid but transient burst of glutamate, followed by an increase in BDNF release and activation of downstream signaling pathways that stimulate synapse formation. Recent work demonstrates that the rapid-acting antidepressant effects of scopolamine, a muscarinic receptor antagonist, are also associated with increased glutamate transmission and synapse formation. These findings have resulted in testing and identification of additional targets and agents that influence glutamate transmission and have rapid antidepressant actions in rodent models and in clinical trials. Together these studies have created tremendous excitement and hope for a new generation of rapid, efficacious antidepressants.

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