scholarly journals Cirbp-PSD95 Axis Protects Against Hypobaric Hypoxia-Induced Aberrant Morphology of Hippocampal Dendritic Spines and Cognitive Deficits

2020 ◽  
Author(s):  
Yang Zhou ◽  
Huanyu Lu ◽  
Ying Liu ◽  
Zaihua Zhao ◽  
Qian Zhang ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Dendritic Spine ◽  
Cognitive Abilities ◽  
Hypobaric Hypoxia ◽  
Rna Binding ◽  
Cognitive Outcomes ◽  
Spine Injury ◽  
Spine Density ◽  
Hypoxia Exposure ◽  
Ca1 Region

Abstract Hypobaric hypoxia (HH) is a typical characteristic of high altitude environment and causes a spectrum of pathophysiological effects, including headaches, gliovascular dysfunction and cognitive slowing. Here, we sought to understand the mechanisms underlying cognitive deficits under HH exposure. Our results showed that HH exposure impaired cognitive function and suppressed dendritic spine density accompanied with increased neck length in both basal and apical hippocampal CA1 region neurons. The expression of PSD95, a critical synaptic scaffolding molecule, is down-regulated by hypoxia exposure and post-transcriptionally controlled by cold-inducible RNA-binding protein (Cirbp) through 3’-UTR region binding. PSD95 expressing alleviates hypoxia-induced neuron dendritic spine plasticity abnormality and memory impairment. Moreover, overexpressed Cirbp in hippocampus rescues hypoxia-induced loss of PSD95 and attenuates hypoxia-induced dendritic spine injury and cognitive outcomes. Thus, our findings reveal a novel mechanism where Cirbp-PSD-95 axis appears to play a key role in hypoxia-induced cognitive abilities impairment in brain.

scholarly journals Cirbp-PSD95 axis protects against hypobaric hypoxia-induced aberrant morphology of hippocampal dendritic spines and cognitive deficits

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Yang Zhou ◽  
Huanyu Lu ◽  
Ying Liu ◽  
Zaihua Zhao ◽  
Qian Zhang ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Dendritic Spine ◽  
Hippocampal Neurons ◽  
Hypobaric Hypoxia ◽  
Rna Binding ◽  
Spine Injury ◽  
Spine Density ◽  
Hypoxia Exposure ◽  
Ca1 Region ◽  
Hippocampal Ca1 Region

AbstractHypobaric hypoxia (HH) is a typical characteristic of high altitude environment and causes a spectrum of pathophysiological effects, including headaches, gliovascular dysfunction and cognitive retardation. Here, we sought to understand the mechanisms underlying cognitive deficits under HH exposure. Our results showed that hypobaric hypoxia exposure impaired cognitive function and suppressed dendritic spine density accompanied with increased neck length in both basal and apical hippocampal CA1 region neurons in mice. The expression of PSD95, a vital synaptic scaffolding molecule, is down-regulated by hypobaric hypoxia exposure and post-transcriptionally regulated by cold-inducible RNA-binding protein (Cirbp) through 3′-UTR region binding. PSD95 expressing alleviates hypoxia-induced dendritic spine morphology changes of hippocampal neurons and memory deterioration. Moreover, overexpressed Cirbp in hippocampus rescues HH-induced abnormal expression of PSD95 and attenuates hypoxia-induced dendritic spine injury and cognitive retardation. Thus, our findings reveal a novel mechanism that Cirbp-PSD-95 axis appears to play an essential role in HH-induced cognitive dysfunction in mice.

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.

scholarly journals Letrozole Potentiates Mitochondrial and Dendritic Spine Impairments Induced byβAmyloid

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
P. K.-Y. Chang ◽  
S. Boridy ◽  
R. A. McKinney ◽  
D. Maysinger
Keyword(s):  
Aromatase Inhibitor ◽  
Dendritic Spine ◽  
Cognitive Abilities ◽  
Mitochondrial Morphology ◽  
Spine Density ◽  
Postsynaptic Protein ◽  
Letrozole Treatment ◽  
Mitochondrial Volume ◽  
Synaptic Structures ◽  
Spine Number

Reduced estrogens, either through aging or postsurgery breast cancer treatment with the oral nonsteroidal aromatase inhibitor letrozole, are linked with declined cognitive abilities. However, a direct link between letrozole and neuronal deficits induced by pathogenic insults associated with aging such as beta amyloid (Aβ1–42) has not been established. The objective of this study was to determine if letrozole aggravates synaptic deficits concurrent withAβ1–42insult. We examined the effects of letrozole and oligomericAβ1–42treatment in dissociated and organotypic hippocampal slice cultures. Changes in glial cell morphology, neuronal mitochondria, and synaptic structures upon letrozole treatment were monitored by confocal microscopy, as they were shown to be affected byAβ1–42oligomers. OligomericAβ1–42or letrozole alone caused decreases in mitochondrial volume, dendritic spine density, synaptophysin (synaptic marker), and the postsynaptic protein, synaptopodin. Here, we demonstrated that mitochondrial and synaptic structural deficits were exacerbated when letrozole therapy was combined withAβ1–42treatment. Our novel findings suggest that letrozole may increase neuronal susceptibility to pathological insults, such as oligomericAβ1–42in Alzheimer’s disease (AD). These changes in dendritic spine number, synaptic protein expression, and mitochondrial morphology may, in part, explain the increased prevalence of cognitive decline associated with aromatase inhibitor use.

scholarly journals Repeated intermittent administration of (R)-ketamine during juvenile and adolescent stages prevents schizophrenia-relevant phenotypes in adult offspring after maternal immune activation: a role of TrkB signaling

2022 ◽  
Author(s):  
Yunfei Tan ◽  
Yuko Fujita ◽  
Yaoyu Pu ◽  
Lijia Chang ◽  
Youge Qu ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Immune Activation ◽  
Dendritic Spine ◽  
Poly I:C ◽  
Adult Offspring ◽  
Spine Density ◽  
Intermittent Administration ◽  
Maternal Immune Activation ◽  
Dendritic Spine Density

AbstractMaternal immune activation (MIA) plays a role in the etiology of schizophrenia. MIA by prenatal exposure of polyinosinic:polycytidylic acid [poly(I:C)] in rodents caused behavioral and neurobiological changes relevant to schizophrenia in adult offspring. We investigated whether the novel antidepressant (R)-ketamine could prevent the development of psychosis-like phenotypes in adult offspring after MIA. We examined the effects of (R)-ketamine (10 mg/kg/day, twice weekly for 4 weeks) during juvenile and adolescent stages (P28–P56) on the development of cognitive deficits, loss of parvalbumin (PV)-immunoreactivity in the medial prefrontal cortex (mPFC), and decreased dendritic spine density in the mPFC and hippocampus from adult offspring after prenatal poly(I:C) exposure. Furthermore, we examined the role of TrkB in the prophylactic effects of (R)-ketamine. Repeated intermittent administration of (R)-ketamine during juvenile and adolescent stages significantly blocked the development of cognitive deficits, reduced PV-immunoreactivity in the prelimbic (PrL) of mPFC, and decreased dendritic spine density in the PrL of mPFC, CA3 and dentate gyrus of the hippocampus from adult offspring after prenatal poly(I:C) exposure. Furthermore, pretreatment with ANA-12 (TrkB antagonist: twice weekly for 4 weeks) significantly blocked the beneficial effects of (R)-ketamine on cognitive deficits of adult offspring after prenatal poly(I:C) exposure. These data suggest that repeated intermittent administration of (R)-ketamine during juvenile and adolescent stages could prevent the development of psychosis in adult offspring after MIA. Therefore, (R)-ketamine would be a potential prophylactic drug for young subjects with high-risk for psychosis.

scholarly journals P3-380: Dendritic spine density deficits in the hippocampal CA1 region of young Tg2576 mice are ameliorated with the PDE9A inhibitor PF-04447943

2010 ◽  
Vol 6 ◽  
pp. S563-S564 ◽  
Author(s):  
Robin J. Kleiman ◽  
Thomas A. Lanz ◽  
James E. Finley ◽  
Susan E. Bove ◽  
Mark J. Majchrzak ◽  
...  
Keyword(s):  
Dendritic Spine ◽  
Spine Density ◽  
Ca1 Region ◽  
Hippocampal Ca1 Region ◽  
Dendritic Spine Density ◽  
Hippocampal Ca1 ◽  
Tg2576 Mice

Pharmacologic manipulation of complement receptor 3 prevents dendritic spine loss and cognitive impairment after acute cranial radiation

2020 ◽  
Author(s):  
Joshua J. Hinkle ◽  
John A. Olschowka ◽  
Jacqueline P. Williams ◽  
M. Kerry O’Banion
Keyword(s):  
Quality Of Life ◽  
Cognitive Impairment ◽  
Cognitive Deficits ◽  
Dendritic Spine ◽  
Cranial Irradiation ◽  
Complement Receptor ◽  
Spine Density ◽  
Male Mice ◽  
Complement Receptor 3

AbstractCranial irradiation induces healthy tissue damage that can lead to neurocognitive complications and negatively impact patient quality of life. One type of damage associated with cognitive impairment is loss of neuronal spine density. Based on developmental and disease studies implicating microglia and complement in dendritic spine loss, we hypothesized that irradiation-mediated spine loss is microglial complement receptor 3 (CR3)-dependent, and associated with late-delayed cognitive deficits. Utilizing a model of cranial irradiation (acute, 10 Gy gamma) in C57BL/6 mice we found that male mice demonstrate irradiation-mediated spine loss and cognitive deficits whereas female mice and CR3 knockout mice do not. Moreover, pharmacological blockade of CR3 with leukadherin-1 (LA1) prevented these changes in irradiated male mice. Interestingly, CR3 KO mice showed reduced behavioral task performance suggesting that CR3 is important for normal learning and memory. Improving our understanding of irradiation-mediated mechanisms and sexual dimorphic responses is essential for the identification of novel therapeutics to reduce irradiation-induced cognitive decline and improve patient quality of life.

scholarly journals Caspase-6-cleaved Tau fails to induce Tau hyperphosphorylation and aggregation, neurodegeneration, glial inflammation, and cognitive deficits

2021 ◽  
Vol 12 (3) ◽  
Author(s):  
Anastasia Noël ◽  
Bénédicte Foveau ◽  
Andréa C. LeBlanc
Keyword(s):  
Cognitive Deficits ◽  
Tau Hyperphosphorylation ◽  
Spine Density ◽  
Tau Pathology ◽  
Ca1 Region ◽  
Hippocampal Ca1 Region ◽  
Hippocampal Ca1 ◽  
Age Dependent ◽  
Cornu Ammonis ◽  
Caspase 6

AbstractActive Caspase-6 (Casp6) and Tau cleaved by Casp6 at amino acids 402 (Tau∆D402) and 421 (Tau∆D421) are present in early Alzheimer disease intraneuronal neurofibrillary tangles, which are made primarily of filamentous Tau aggregates. To assess whether Casp6 cleavage of Tau contributes to Tau pathology and Casp6-mediated age-dependent cognitive impairment, we generated transgenic knock-in mouse models that conditionally express full-length human Tau (hTau) 0N4R only (CTO) or together with human Casp6 (hCasp6) (CTC). Region-specific hippocampal and cortical hCasp6 and hTau expression were confirmed with western blot and immunohistochemistry in 2–25-month-old brains. Casp6 activity was confirmed with Tau∆D421 and Tubulin cleaved by Casp6 immunopositivity in 3–25-month-old CTC, but not in CTO, brains. Immunoprecipitated Tau∆D402 was detected in both CTC and CTO brains, but was more abundant in CTC brains. Intraneuronal hippocampal Tau hyperphosphorylation at S202/T205, S422, and T231, and Tau conformational change were absent in both CTC and CTO brains. A slight accumulation of Tau phosphorylated at S396/404 and S202 was observed in Cornu Ammonis 1 (CA1) hippocampal neuron soma of CTC compared to CTO brains. Eighteen-month-old CTC brains showed rare argentophilic deposits that increased by 25 months, whereas CTO brains only displayed them sparsely at 25 months. Tau microtubule binding was equivalent in CTC and CTO hippocampi. Episodic and spatial memory measured with novel object recognition and Barnes maze, respectively, remained normal in 3–25-month-old CTC and CTO mice, in contrast to previously observed impairments in ACL mice expressing equivalent levels of hCasp6 only. Consistently, the CTC and CTO hippocampal CA1 region displayed equivalent dendritic spine density and no glial inflammation. Together, these results reveal that active hCasp6 co-expression with hTau generates Tau cleavage and rare age-dependent argentophilic deposits but fails to induce cognitive deficits, neuroinflammation, and Tau pathology.

scholarly journals Simultaneous Changes of Spatial Memory and Spine Density after Intrahippocampal Administration of Fibrillar Aβ1–42to the Rat Brain

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Emőke Borbély ◽  
János Horváth ◽  
Szabina Furdan ◽  
Zsolt Bozsó ◽  
Botond Penke ◽  
...  
Keyword(s):  
Spatial Memory ◽  
Dendritic Spine ◽  
Density Measurement ◽  
Rat Hippocampus ◽  
Learning Ability ◽  
Spine Density ◽  
Ca1 Region ◽  
Dendritic Spine Density ◽  
Intrahippocampal Injection ◽  
The Brain

Several animal models of Alzheimer’s disease have been used in laboratory experiments. Intrahippocampal injection of fibrillar amyloid-beta (fAβ) peptide represents one of the most frequently used models, mimicking Aβdeposits in the brain. In our experiment synthetic fAβ1–42peptide was administered to rat hippocampus. The effect of the Aβpeptide on spatial memory and dendritic spine density was studied. The fAβ1–42-treated rats showed decreased spatial learning ability measured in Morris water maze (MWM). Simultaneously, fAβ1–42caused a significant reduction of the dendritic spine density in the rat hippocampus CA1 region. The decrease of learning ability and the loss of spine density were in good correlation. Our results prove that both methods (MWM and dendritic spine density measurement) are suitable for studying Aβ-triggered neurodegeneration processes.

scholarly journals Simulated aeromedical evacuation exacerbates burn induced lung injury: targeting mitochondrial DNA for reversal

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Meng-Jing Xiao ◽  
Xiao-Fang Zou ◽  
Bin Li ◽  
Bao-Long Li ◽  
Shi-Jian Wu ◽  
...  
Keyword(s):  
Lung Injury ◽  
Nlrp3 Inflammasome ◽  
Hypobaric Hypoxia ◽  
Dnase I ◽  
Treatment Intervention ◽  
Aeromedical Evacuation ◽  
Hypoxia Exposure ◽  
Histopathological Evaluation ◽  
Lung Injuries ◽  
Mda Content

Abstract Background Aeromedical evacuation of patients with burn trauma is an important transport method in times of peace and war, during which patients are exposed to prolonged periods of hypobaric hypoxia; however, the effects of such exposure on burn injuries, particularly on burn-induced lung injuries, are largely unexplored. This study aimed to determine the effects of hypobaric hypoxia on burn-induced lung injuries and to investigate the underlying mechanism using a rat burn model. Methods A total of 40 male Wistar rats were randomly divided into four groups (10 in each group): sham burn (SB) group, burn in normoxia condition (BN) group, burn in hypoxia condition (BH) group, and burn in hypoxia condition with treatment intervention (BHD) group. Rats with 30% total body surface area burns were exposed to hypobaric hypoxia (2000 m altitude simulation) or normoxia conditions for 4 h. Deoxyribonuclease I (DNase I) was administered systemically as a treatment intervention. Systemic inflammatory mediator and mitochondrial deoxyribonucleic acid (mtDNA) levels were determined. A histopathological evaluation was performed and the acute lung injury (ALI) score was determined. Malonaldehyde (MDA) content, myeloperoxidase (MPO) activity, and the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome level were determined in lung tissues. Data among groups were compared using analysis of variance followed by Tukey’s test post hoc analysis. Results Burns resulted in a remarkably higher level of systemic inflammatory cytokines and mtDNA release, which was further heightened by hypobaric hypoxia exposure (P < 0.01). Moreover, hypobaric hypoxia exposure gave rise to increased NLRP3 inflammasome expression, MDA content, and MPO activity in the lung (P < 0.05 or P < 0.01). Burn-induced lung injuries were exacerbated, as shown by the histopathological evaluation and ALI score (P < 0.01). Administration of DNase I markedly reduced mtDNA release and systemic inflammatory cytokine production. Furthermore, the NLRP3 inflammasome level in lung tissues was decreased and burn-induced lung injury was ameliorated (P < 0.01). Conclusions Our results suggested that simulated aeromedical evacuation further increased burn-induced mtDNA release and exacerbated burn-induced inflammation and lung injury. DNase I reduced the release of mtDNA, limited mtDNA-induced systemic inflammation, and ameliorated burn-induced ALI. The intervening mtDNA level is thus a potential target to protect from burn-induced lung injury during aeromedical conditions and provides safer air evacuations for severely burned patients.

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