Antidepressant effects of acupoint stimulation and fluoxetine by increasing dendritic arborization and spine density in CA1 hippocampal neurons of socially isolated rats

2018 ◽  
Vol 675 ◽  
pp. 48-53 ◽  
Author(s):  
Amalia Dávila-Hernández ◽  
Sergio R. Zamudio ◽  
Lucía Martínez-Mota ◽  
Roberto González-González ◽  
Eduardo Ramírez-San Juan
Keyword(s):  
Hippocampal Neurons ◽  
Dendritic Arborization ◽  
Spine Density ◽  
Antidepressant Effects ◽  
Socially Isolated ◽  
Acupoint Stimulation

scholarly journals NRF2 Activation Ameliorates Oxidative Stress and Improves Mitochondrial Function and Synaptic Plasticity, and in A53T α-Synuclein Hippocampal Neurons

Antioxidants ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 26
Author(s):  
Mikah S. Brandes ◽  
Jonathan A. Zweig ◽  
Anita Tang ◽  
Nora E. Gray
Keyword(s):  
Oxidative Stress ◽  
Synaptic Plasticity ◽  
Mitochondrial Function ◽  
Hippocampal Neurons ◽  
Neuronal Loss ◽  
Dimethyl Fumarate ◽  
Dendritic Arborization ◽  
Therapeutic Interventions ◽  
Spine Density ◽  
Nrf2 Activator

In Parkinson’s disease (PD), brain oxidative stress and mitochondrial dysfunction contribute to neuronal loss as well as motor and cognitive deficits. The transcription factor NRF2 has emerged as a promising therapeutic target in PD because it sits at the intersection of antioxidant and mitochondrial pathways. Here, we investigate the effects of modulating NRF2 activity in neurons isolated from a A53T α-synuclein (A53TSyn) mouse model of synucleinopathy. Embryonic hippocampal neurons were isolated from A53TSyn mice and their wild type (WT) littermates. Neurons were treated with either the NRF2 activator dimethyl fumarate (DMF) or the NRF2 inhibitor ML385. Reactive oxygen species (ROS), dendritic arborization and dendritic spine density were quantified. Mitochondrial bioenergetics were also profiled in these neurons. A53TSyn neurons had increased ROS and reduced basal and maximal mitochondrial respiration relative to WT neurons. A53TSyn neurons also displayed decreased dendritic arborization and reduced spine density. Treatment with DMF reduced ROS levels and improved both mitochondrial function and arborization, while inhibition of NRF2 with ML385 exacerbated these endpoints. Modulation of NRF2 activity had a significant effect on mitochondrial function, oxidative stress, and synaptic plasticity in A53TSyn neurons. These data suggest that NRF2 may be a viable target for therapeutic interventions in PD.

Neurotrophic Properties of Silexan, an Essential Oil from the Flowers of Lavender-Preclinical Evidence for Antidepressant-Like Properties

2020 ◽  
Vol 54 (01) ◽  
pp. 37-46
Author(s):  
Kristina Friedland ◽  
Giacomo Silani ◽  
Anita Schuwald ◽  
Carola Stockburger ◽  
Egon Koch ◽  
...  
Keyword(s):  
Essential Oil ◽  
Hippocampal Neurons ◽  
Day Treatment ◽  
Neuronal Cell ◽  
Antidepressant Activity ◽  
In Vivo Models ◽  
Antidepressant Effects ◽  
Primary Hippocampal Neurons

Abstract Background Silexan, a special essential oil from flowering tops of lavandula angustifolia, is used to treat subsyndromal anxiety disorders. In a recent clinical trial, Silexan also showed antidepressant effects in patients suffering from mixed anxiety-depression (ICD-10 F41.2). Since preclinical data explaining antidepressant properties of Silexan are missing, we decided to investigate if Silexan also shows antidepressant-like effects in vitro as well as in vivo models. Methods We used the forced swimming test (FST) in rats as a simple behavioral test indicative of antidepressant activity in vivo. As environmental events and other risk factors contribute to depression through converging molecular and cellular mechanisms that disrupt neuronal function and morphology—resulting in dysfunction of the circuitry that is essential for mood regulation and cognitive function—we investigated the neurotrophic properties of Silexan in neuronal cell lines and primary hippocampal neurons. Results The antidepressant activity of Silexan (30 mg/kg BW) in the FST was comparable to the tricyclic antidepressant imipramine (20 mg/kg BW) after 9-day treatment. Silexan triggered neurite outgrowth and synaptogenesis in 2 different neuronal cell models and led to a significant increase in synaptogenesis in primary hippocampal neurons. Silexan led to a significant phosphorylation of protein kinase A and subsequent CREB phosphorylation. Conclusion Taken together, Silexan demonstrates antidepressant-like effects in cellular as well as animal models for antidepressant activity. Therefore, our data provides preclinical evidence for the clinical antidepressant effects of Silexan in patients with mixed depression and anxiety.

scholarly journals RTP801/REDD1 contributes to neuroinflammation severity and memory impairments in Alzheimer’s disease

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Leticia Pérez-Sisqués ◽  
Anna Sancho-Balsells ◽  
Júlia Solana-Balaguer ◽  
Genís Campoy-Campos ◽  
Marcel Vives-Isern ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Hippocampal Neurons ◽  
Mrna Levels ◽  
Spine Density ◽  
Memory Impairments ◽  
Protein Levels ◽  
Synaptic Markers ◽  
5Xfad Mice

AbstractRTP801/REDD1 is a stress-regulated protein whose upregulation is necessary and sufficient to trigger neuronal death. Its downregulation in Parkinson’s and Huntington’s disease models ameliorates the pathological phenotypes. In the context of Alzheimer’s disease (AD), the coding gene for RTP801, DDIT4, is responsive to Aβ and modulates its cytotoxicity in vitro. Also, RTP801 mRNA levels are increased in AD patients’ lymphocytes. However, the involvement of RTP801 in the pathophysiology of AD has not been yet tested. Here, we demonstrate that RTP801 levels are increased in postmortem hippocampal samples from AD patients. Interestingly, RTP801 protein levels correlated with both Braak and Thal stages of the disease and with GFAP expression. RTP801 levels are also upregulated in hippocampal synaptosomal fractions obtained from murine 5xFAD and rTg4510 mice models of the disease. A local RTP801 knockdown in the 5xFAD hippocampal neurons with shRNA-containing AAV particles ameliorates cognitive deficits in 7-month-old animals. Upon RTP801 silencing in the 5xFAD mice, no major changes were detected in hippocampal synaptic markers or spine density. Importantly, we found an unanticipated recovery of several gliosis hallmarks and inflammasome key proteins upon neuronal RTP801 downregulation in the 5xFAD mice. Altogether our results suggest that RTP801 could be a potential future target for theranostic studies since it could be a biomarker of neuroinflammation and neurotoxicity severity of the disease and, at the same time, a promising therapeutic target in the treatment of AD.

scholarly journals TheGαoActivator Mastoparan-7 Promotes Dendritic Spine Formation in Hippocampal Neurons

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Valerie T. Ramírez ◽  
Eva Ramos-Fernández ◽  
Nibaldo C. Inestrosa
Keyword(s):  
Protein Kinase ◽  
Dendritic Spine ◽  
Hippocampal Neurons ◽  
Biological Effects ◽  
Critical Role ◽  
Head Width ◽  
Dependent Manner ◽  
Spine Density ◽  
Dendritic Spine Density

Mastoparan-7 (Mas-7), an analogue of the peptide mastoparan, which is derived from wasp venom, is a direct activator ofPertussis toxin-(PTX-) sensitive G proteins. Mas-7 produces several biological effects in different cell types; however, little is known about how Mas-7 influences mature hippocampal neurons. We examined the specific role of Mas-7 in the development of dendritic spines, the sites of excitatory synaptic contact that are crucial for synaptic plasticity. We report here that exposure of hippocampal neurons to a low dose of Mas-7 increases dendritic spine density and spine head width in a time-dependent manner. Additionally, Mas-7 enhances postsynaptic density protein-95 (PSD-95) clustering in neurites and activatesGαosignaling, increasing the intracellular Ca2+concentration. To define the role of signaling intermediates, we measured the levels of phosphorylated protein kinase C (PKC), c-Jun N-terminal kinase (JNK), and calcium-calmodulin dependent protein kinase IIα(CaMKIIα) after Mas-7 treatment and determined that CaMKII activation is necessary for the Mas-7-dependent increase in dendritic spine density. Our results demonstrate a critical role forGαosubunit signaling in the regulation of synapse formation.

scholarly journals Ketamine produces antidepressant-like effects through phosphorylation-dependent nuclear export of histone deacetylase 5 (HDAC5) in rats

2015 ◽  
Vol 112 (51) ◽  
pp. 15755-15760 ◽  
Author(s):  
Miyeon Choi ◽  
Seung Hoon Lee ◽  
Sung Eun Wang ◽  
Seung Yeon Ko ◽  
Mihee Song ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Nuclear Export ◽  
Hippocampal Neurons ◽  
Transcriptional Activity ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Calmodulin Kinase ◽  
Defective Mutant ◽  
Antidepressant Effects

Ketamine produces rapid antidepressant-like effects in animal assays for depression, although the molecular mechanisms underlying these behavioral actions remain incomplete. Here, we demonstrate that ketamine rapidly stimulates histone deacetylase 5 (HDAC5) phosphorylation and nuclear export in rat hippocampal neurons through calcium/calmodulin kinase II- and protein kinase D-dependent pathways. Consequently, ketamine enhanced the transcriptional activity of myocyte enhancer factor 2 (MEF2), which leads to regulation of MEF2 target genes. Transfection of a HDAC5 phosphorylation-defective mutant (Ser259/Ser498 replaced by Ala259/Ala498, HDAC5-S/A), resulted in resistance to ketamine-induced nuclear export, suppression of ketamine-mediated MEF2 transcriptional activity, and decreased expression of MEF2 target genes. Behaviorally, viral-mediated hippocampal knockdown of HDAC5 blocked or occluded the antidepressant effects of ketamine both in unstressed and stressed animals. Taken together, our results reveal a novel role of HDAC5 in the actions of ketamine and suggest that HDAC5 could be a potential mechanism contributing to the therapeutic actions of ketamine.

scholarly journals CREB Activation Mediates Plasticity in Cultured Hippocampal Neurons

1998 ◽  
Vol 6 (3) ◽  
pp. 1-7 ◽  
Author(s):  
Menahem Segal ◽  
Diane D. Murphy
Keyword(s):  
Cyclic Amp ◽  
Dendritic Spines ◽  
Hippocampal Neurons ◽  
Long Term Potentiation ◽  
Spine Density ◽  
Creb Phosphorylation ◽  
Molecular Events ◽  
Term Potentiation ◽  
Element Binding Protein ◽  
Responsive Element

Activation of cyclic AMP dependent kinase is believed to mediate slow onset, long-term potentiation (LTP) in central neurons. Cyclic- AMP activates a cascade of molecular events leading to phosphorylation of the nuclear cAMP responsive element binding protein (pCREB). Whereas a variety of stimuli lead to activation of CREB, the molecular processes downstream of CREB, which may be relevant to neuronal plasticity, are yet largely unknown. We have recently found that following exposure to estradiol, pCREB mediates the large increase in dendritic spine density in cultured rat hippocampal neurons. We now extend these observations to include other stimuli, such as bicuculline, that cause the formation of new dendritic spines. Such stimuli share with estradiol the same mechanism of action in that both require activity-dependent CREB phosphorylation. Our observations suggest that CREB phosphorylation is a necessary, but perhaps not sufficient, step in the process leading to the generation of new dendritic spines and perhaps to functional plasticity as well.

scholarly journals The Polyadenosine RNA Binding Protein ZC3H14 is Required in Mice for Proper Dendritic Spine Density

2020 ◽  
Author(s):  
Stephanie K. Jones ◽  
Jennifer Rha ◽  
Sarah Kim ◽  
Kevin J. Morris ◽  
Omotola F. Omotade ◽  
...  
Keyword(s):  
Dendritic Spine ◽  
Hippocampal Neurons ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Spine Density ◽  
Dendritic Spine Density

AbstractZC3H14 (Zinc finger CysCysCysHis domain-containing protein 14), an evolutionarily conserved member of a class of tandem zinc finger (CCCH) polyadenosine (polyA) RNA binding proteins, is associated with a form of heritable, nonsyndromic autosomal recessive intellectual disability. Previous studies of a loss of function mouse model, Zc3h14Δex13/Δex13, provide evidence that ZC3H14 is essential for proper brain function, specifically for working memory. To expand on these findings, we analyzed the dendrites and dendritic spines of hippocampal neurons from Zc3h14Δex13/Δex13 mice, both in situ and in vitro. These studies reveal that loss of ZC3H14 is associated with a decrease in total spine density in hippocampal neurons in vitro as well as in the dentate gyrus of 5-month old mice analyzed in situ. This reduction in spine density in vitro results from a decrease in the number of mushroom-shaped spines, which is rescued by exogenous expression of ZC3H14. We next performed biochemical analyses of synaptosomes prepared from whole wild-type and Zc3h14Δex13/Δex13 mouse brains to determine if there are changes in steady state levels of postsynaptic proteins upon loss of ZC3H14. We found that ZC3H14 is present within synaptosomes and that a crucial postsynaptic protein, CaMKIIα, is significantly increased in these synaptosomal fractions upon loss of ZC3H14. Together, these results demonstrate that ZC3H14 is necessary for proper dendritic spine density in cultured hippocampal neurons and in some regions of the mouse brain. These findings provide insight into how a ubiquitously expressed RNA binding protein leads to neuronal-specific defects that result in brain dysfunction.

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