scholarly journals Age-dependent changes of p53 and p63 immunoreactivities in the mouse hippocampus

2019 ◽  
Vol 35 (1) ◽  
Author(s):  
Tae-Kyeong Lee ◽  
Young Eun Park ◽  
Cheol Woo Park ◽  
Bora Kim ◽  
Jae-Chul Lee ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Pyramidal Neurons ◽  
Granule Cells ◽  
Normal Aging ◽  
Aged Mice ◽  
Adult Mice ◽  
Fluoro Jade B ◽  
Neuronal Distribution ◽  
P53 Immunoreactivity ◽  
Young Mice

Abstract P53 and its family member p63 play important roles in cellular senescence and organismal aging. In this study, p53 and p63 immunoreactivity were examined in the hippocampus of young, adult and aged mice by using immunohistochemistry. In addition, neuronal distribution and degeneration was examined by NeuN immunohistochemistry and fluoro-Jade B fluorescence staining. Strong p53 immunoreactivity was mainly expressed in pyramidal and granule cells of the hippocampus in young mice. p53 immunoreactivity in the pyramidal and granule cells was significantly reduced in the adult mice. In the aged mice, p53 immunoreactivity in the pyramidal and granule cells was more significantly decreased. p63 immunoreactivity was strong in the pyramidal and granule cells in the young mice. p63 immunoreactivity in these cells was apparently and gradually decreased with age, showing that p63 immunoreactivity in the aged granule cells was hardly shown. However, numbers of pyramidal neurons and granule cells were not significantly decreased in the aged mice with normal aging. Taken together, this study indicates that there are no degenerative neurons in the hippocampus during normal aging, showing that p53 and p63 immunoreactivity in hippocampal neurons was progressively reduced during normal aging, which might be closely related to the normal aging processes.

scholarly journals Dual Mkk4 and Mkk7 Gene Deletion in Adult Mouse Causes an Impairment of Hippocampal Immature Granule Cells

2021 ◽  
Vol 22 (17) ◽  
pp. 9545
Author(s):  
Rubén Darío Castro-Torres ◽  
Jordi Olloquequi ◽  
Miren Etchetto ◽  
Pablo Caruana ◽  
Luke Steele ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Hippocampal Neurons ◽  
Gene Deletion ◽  
Granule Cells ◽  
Hippocampal Neurogenesis ◽  
Mitogen Activated Protein Kinase ◽  
Jnk Pathway ◽  
Adult Mice ◽  
Mitogen Activated Protein ◽  
Genetic Deletion

(1) Background: The c-Jun-NH2-terminal protein kinase (JNK) is a mitogen-activated protein kinase involved in regulating physiological processes in the central nervous system. However, the dual genetic deletion of Mkk4 and Mkk7 (upstream activators of JNK) in adult mice is not reported. The aim of this study was to induce the genetic deletion of Mkk4/Mkk7 in adult mice and analyze their effect in hippocampal neurogenesis. (2) Methods: To achieve this goal, Actin-CreERT2 (Cre+/−), Mkk4flox/flox, Mkk7flox/flox mice were created. The administration of tamoxifen in these 2-month-old mice induced the gene deletion (Actin-CreERT2 (Cre+/−), Mkk4∆/∆, Mkk7∆/∆ genotype), which was verified by PCR, Western blot, and immunohistochemistry techniques. (3) Results: The levels of MKK4/MKK7 at 7 and 14 days after tamoxifen administration were not eliminated totally in CNS, unlike what happens in the liver and heart. These data could be correlated with the high levels of these proteins in CNS. In the hippocampus, the deletion of Mkk4/Mkk7 induced a misalignment position of immature hippocampal neurons together with alterations in their dendritic architecture pattern and maturation process jointly to the diminution of JNK phosphorylation. (4) Conclusion: All these data supported that the MKK4/MKK7–JNK pathway has a role in adult neurogenic activity.

scholarly journals Delayed Demyelination and Impaired Remyelination in Aged Mice in the Cuprizone Model

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 945 ◽  
Author(s):  
Stefan Gingele ◽  
Florian Henkel ◽  
Sandra Heckers ◽  
Thiemo M. Moellenkamp ◽  
Martin W. Hümmert ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Animal Model ◽  
Animal Models ◽  
Corpus Callosum ◽  
Mature Adult ◽  
Aged Mice ◽  
Adult Mice ◽  
Regenerative Therapies ◽  
Young Mice

To unravel the failure of remyelination in multiple sclerosis (MS) and to test promising remyelinating treatments, suitable animal models like the well-established cuprizone model are required. However, this model is only standardized in young mice. This does not represent the typical age of MS patients. Furthermore, remyelination is very fast in young mice, hindering the examination of effects of remyelination-promoting agents. Thus, there is the need for a better animal model to study remyelination. We therefore aimed to establish the cuprizone model in aged mice. 6-month-old C57BL6 mice were fed with different concentrations of cuprizone (0.2–0.6%) for 5–6.5 weeks. De- and remyelination in the medial and lateral parts of the corpus callosum were analyzed by immunohistochemistry. Feeding aged mice 0.4% cuprizone for 6.5 weeks resulted in the best and most reliable administration scheme with virtually complete demyelination of the corpus callosum. This was accompanied by a strong accumulation of microglia and near absolute loss of mature oligodendrocytes. Subsequent remyelination was initially robust but remained incomplete. The remyelination process in mature adult mice better represents the age of MS patients and offers a better model for the examination of regenerative therapies.

scholarly journals Enhanced inflammation in aged mice following infection with Streptococcus pneumoniae is associated with decreased IL-10 and augmented chemokine production

2015 ◽  
Vol 308 (6) ◽  
pp. L539-L549 ◽  
Author(s):  
Andrew E. Williams ◽  
Ricardo J. José ◽  
Jeremy S. Brown ◽  
Rachel C. Chambers
Keyword(s):  
Streptococcus Pneumoniae ◽  
Young Adult ◽  
Inflammatory Responses ◽  
Severe Pneumonia ◽  
Chemokine Production ◽  
Aged Mice ◽  
Adult Mice ◽  
The Impact ◽  
Bacterial Outgrowth ◽  
Young Mice

Streptococcus pneumoniae is the most common cause of severe pneumonia in the elderly. However, the impact of aging on the innate inflammatory response to pneumococci is poorly defined. We compared the innate immune response in old vs. young adult mice following infection with S. pneumoniae. The accumulation of neutrophils recovered from bronchoalveolar lavage fluid and lung homogenates was increased in aged compared with young adult mice, although bacterial outgrowth was similar in both age groups, as were markers of microvascular leak. Aged mice had similar levels of IL-1β, TNF, IFN-γ, IL-17, and granulocyte colony-stimulating factor following S. pneumoniae infection, compared with young mice, but increased levels of the chemokines CXCL9, CXCL12, CCL3, CCL4, CCL5, CCL11, and CCL17. Moreover, levels of IL-10 were significantly lower in aged animals. Neutralization of IL-10 in infected young mice was associated with increased neutrophil recruitment but no decrease in bacterial outgrowth. Furthermore, IL-10 neutralization resulted in increased levels of CCL3, CCL5, and CXCL10. We conclude that aging is associated with enhanced inflammatory responses following S. pneumoniae infection as a result of a compromised immunomodulatory cytokine response.

scholarly journals Neonatal oxytocin impacts hippocampal network development and restores adult social memory in a mouse model of autism

2020 ◽  
Author(s):  
Alessandra Bertoni ◽  
Fabienne Schaller ◽  
Roman Tyzio ◽  
Stephane Gaillard ◽  
Francesca Santini ◽  
...  
Keyword(s):  
Mouse Model ◽  
Neurodevelopmental Disorders ◽  
Hippocampal Neurons ◽  
Pyramidal Neurons ◽  
Social Memory ◽  
Strong Impact ◽  
Adult Mice ◽  
Ca3 Neurons ◽  
The Brain ◽  
Deficient Mice

AbstractPrader-Willi (PW) and Schaaf-Yang (SY) syndromes are genetic neurodevelopmental disorders involving MAGEL2 gene. Magel2-deficient mice mimic the symptoms common to both diseases, in particular autistic-like symptoms. Importantly, peripheral administration of oxytocin during infancy cures social deficiency of Magel2-KO mice beyond treatment into adulthood. However, neurobiological alterations related to oxytocin-signaling and responsible for social deficits are poorly explored in mouse models of autism, including Magel2-deficient mice. Moreover, the mechanisms by which neonatal oxytocin-administration improves social behavior remain unknown. Here, by studying Magel2-KO mice, we aim to decipher the mechanisms underlying the PWS/SYS social alterations and their rescue by oxytocin.Hippocampal neurons in Dentate Gyrus and CA2/CA3 regions are associated with social memory engrams involving the oxytocin-system. We have shown that Magel2 and oxytocin-receptor are specifically co-expressed in those neurons during development. Then, in Magel2-deficient adult mice, we showed a deficit of social memory and revealed an increase of spontaneous inhibitory activity of pyramidal neurons, a higher number of somatostatin-positive interneurons and an increase in the number of oxytocin-receptors. We also showed a delay in the GABAergic developmental sequence in CA3 neurons associated with biochemical changes in potassium-chloride cotransporter KCC2. Importantly, we demonstrated a strong impact of neonatal oxytocin administration, rescuing all these neuronal alterations.This study elucidates the mechanisms by which peripheral oxytocin-administration in neonates affects the brain social circuitry. While clinical trials are ongoing, we are demonstrating the therapeutic value of administrating oxytocin in newborns to treat patients with Prader-Willi and Schaaf-Yang syndromes and possibly other neurodevelopmental disorders related to autism.Single sentence summaryThis study reveals how peripheral administration of oxytocin in newborns treats alterations in the brain social circuits described in a mouse model of autism.

scholarly journals Deletion of calcineurin from GFAP-expressing astrocytes impairs excitability of cerebellar and hippocampal neurons through astroglial Na+/K+ ATPase

2019 ◽  
Author(s):  
Laura Tapella ◽  
Teresa Soda ◽  
Lisa Mapelli ◽  
Valeria Bortolotto ◽  
Heather Bondi ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Granule Cells ◽  
Cerebellar Granule Cells ◽  
Normal Growth ◽  
Conditional Knockout ◽  
Protein Levels ◽  
Hippocampal Ca1 ◽  
Neuronal Functions

ABSTRACTAstrocytes perform important housekeeping functions in the nervous system including maintenance of adequate neuronal excitability, although the regulatory mechanisms are currently poorly understood. The astrocytic Ca2+/calmodulin-activated phosphatase calcineurin (CaN) is implicated in the development of reactive gliosis and neuroinflammation, but its roles, including the control of neuronal excitability, in healthy brain is unknown. We have generated a mouse line with conditional knockout (KO) of CaN B1 (CaNB1) in glial fibrillary acidic protein (GFAP)-expressing astrocytes (astroglial calcineurin knock-out, ACN-KO). Here we report that postnatal and astrocyte-specific ablation of CaNB1 did not alter normal growth and development as well as adult neurogenesis. Yet, we found that specific deletion of astrocytic CaN selectively impairs intrinsic neuronal excitability in hippocampal CA1 pyramidal neurons and cerebellar granule cells (CGCs). This impairment was associated with a decrease in after-hyperpolarization in CGC, while passive properties were unchanged, suggesting impairment of K+ homeostasis. Indeed, blockade of Na+/K+-ATPase (NKA) with ouabain phenocopied the electrophysiological alterations observed in ACN-KO CGCs. In addition, NKA activity was significantly lower in cerebellar and hippocampal lysates and in pure astrocytic cultures from ACN-KO mice. While no changes were found in protein levels, NKA activity was inhibited by the specific CaN inhibitor FK506 in both cerebellar lysates and primary astroglia from control mice, suggesting that CaN directly modulates NKA activity and in this manner controls neuronal excitability. In summary, our data provide formal evidence for the notion that astroglia is fundamental for controlling basic neuronal functions and place CaN center-stage as an astrocytic Ca2+-sensitive switch.

scholarly journals Impaired Cognitive Function and Hippocampal Changes Following Chronic Diazepam Treatment in Middle-Aged Mice

2021 ◽  
Vol 13 ◽  
Author(s):  
Tomonori Furukawa ◽  
Yoshikazu Nikaido ◽  
Shuji Shimoyama ◽  
Nozomu Masuyama ◽  
Ayaka Notoya ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Adverse Effects ◽  
Dendritic Spine ◽  
Hippocampal Neurons ◽  
Spine Density ◽  
Middle Aged ◽  
Aged Mice ◽  
Dendritic Spine Density ◽  
Young Mice

Background: Gamma-aminobutyric acid (GABA) type A receptors are positively allosterically modulated by benzodiazepine binding, leading to a potentiated response to GABA. Diazepam (DZP, a benzodiazepine) is widely prescribed for anxiety, epileptic discharge, and insomnia, and is also used as a muscle relaxant and anti-convulsant. However, some adverse effects – such as tolerance, dependence, withdrawal effects, and impairments in cognition and learning – are elicited by the long-term use of DZP. Clinical studies have reported that chronic DZP treatment increases the risk of dementia in older adults. Furthermore, several studies have reported that chronic DZP administration may affect neuronal activity in the hippocampus, dendritic spine structure, and cognitive performance. However, the effects of chronic DZP administration on cognitive function in aged mice is not yet completely understood.Methods: A behavioral test, immunohistochemical analysis of neurogenic and apoptotic markers, dendritic spine density analysis, and long-term potentiation (LTP) assay of the hippocampal CA1 and CA3 were performed in both young (8 weeks old) and middle-aged (12 months old) mice to investigate the effects of chronic DZP administration on cognitive function. The chronic intraperitoneal administration of DZP was performed by implanting an osmotic minipump. To assess spatial learning and memory ability, the Morris water maze test was performed. Dendritic spines were visualized using Lucifer yellow injection into the soma of hippocampal neurons, and spine density was analyzed. Moreover, the effects of exercise on DZP-induced changes in spine density and LTP in the hippocampus were assessed.Results: Learning performance was impaired by chronic DZP administration in middle-aged mice but not in young mice. LTP was attenuated by DZP administration in the CA1 of young mice and the CA3 of middle-aged mice. The spine density of hippocampal neurons was decreased by chronic DZP administration in the CA1 of both young and middle-aged mice as well as in the CA3 of middle-aged mice. Neither neurogenesis nor apoptosis in the hippocampus was affected by chronic DZP administration.Conclusion: The results of this study suggest that the effects of chronic DZP are different between young and middle-aged mice. The chronic DZP-induced memory retrieval performance impairment in middle-aged mice can likely be attributed to decreased LTP and dendritic spine density in hippocampal neurons in the CA3. Notably, prophylactic exercise suppressed the adverse effects of chronic DZP on LTP and spine maintenance in middle-aged mice.

scholarly journals Bcl-2-dependent autophagy disruption during aging impairs amino acid utilization that is restored by hochuekkito

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Miwa Nahata ◽  
Sachiko Mogami ◽  
Hitomi Sekine ◽  
Seiichi Iizuka ◽  
Naoto Okubo ◽  
...  
Keyword(s):  
Amino Acid ◽  
Energy Homeostasis ◽  
Mitochondrial Dynamics ◽  
Negative Regulator ◽  
Aged Mice ◽  
Glucose Levels ◽  
Therapeutic Benefits ◽  
Age Related ◽  
Daily Food ◽  
Young Mice

AbstractChronic undernutrition contributes to the increase in frailty observed among elderly adults, which is a pressing issue in the sector of health care for older people worldwide. Autophagy, an intracellular recycling system, is closely associated with age-related pathologies. Therefore, decreased autophagy in aging could be involved in the disruption of energy homeostasis that occurs during undernutrition; however, the physiological mechanisms underlying this process remain unknown. Here, we showed that 70% daily food restriction (FR) induced fatal hypoglycemia in 23–26-month-old (aged) mice, which exhibited significantly lower hepatic autophagy than 9-week-old (young) mice. The liver expressions of Bcl-2, an autophagy-negative regulator, and Beclin1–Bcl-2 binding, were increased in aged mice compared with young mice. The autophagy inducer Tat-Beclin1 D11, not the mTOR inhibitor rapamycin, decreased the plasma levels of the glucogenic amino acid and restored the blood glucose levels in aged FR mice. Decreased liver gluconeogenesis, body temperature, physical activity, amino acid metabolism, and hepatic mitochondrial dynamics were observed in the aged FR mice. These changes were restored by treatment with hochuekkito that is a herbal formula containing several autophagy-activating ingredients. Our results indicate that Bcl-2 upregulation in the liver during the aging process disturbs autophagy activation, which increases the vulnerability to undernutrition. The promotion of liver autophagy may offer clinical therapeutic benefits to frail elderly patients.

scholarly journals Epipregnanolone as a Positive Modulator of GABAA Receptor in Rat Cerebellar and Hippocampus Neurons

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 791
Author(s):  
Julia Bukanova ◽  
Elena Solntseva ◽  
Rodion Kondratenko ◽  
Eva Kudova
Keyword(s):  
Gabaa Receptor ◽  
Purkinje Cells ◽  
Hippocampal Neurons ◽  
Pyramidal Neurons ◽  
Patch Clamp Technique ◽  
Dual Effect ◽  
Combined Application ◽  
Gabaa Receptor Antagonist ◽  
Positive Modulator ◽  
Endogenous Steroid

Epipregnanolone (3β-hydroxy-5β-pregnan-20-one, Epi) is an endogenous steroid with important physiological effects and high affinity for GABAA receptors. The effect of Epi on GABA-induced chloride current (IGABA) in native neurons has hardly been studied. In this work, we studied the influence of Epi on the IGABA in the Purkinje cells of rat cerebellum and pyramidal neurons of rat hippocampus with the patch clamp technique. We showed that Epi is a positive modulator of the IGABA with EC50 of 5.7 µM in Purkinje cells and 9.3 µM in hippocampal neurons. Epi-induced potentiation of the IGABA was more potent at low vs. high GABA concentrations. Isopregnanolone (3β-hydroxy-5α-pregnan-20-one, Iso) counteracted Epi, reducing its potentiating effect by 2–2.3 times. Flumazenil, a nonsteroidal GABAA receptor antagonist, does not affect the Epi-induced potentiation. Comparison of the potentiating effects of Epi and allopregnanolone (3α-hydroxy-5α-pregnan-20-one, ALLO) showed that ALLO is, at least, a four times more potent positive modulator than Epi. The combined application of ALLO and Epi showed that the effects of these two steroids are not additive. We conclude that Epi has a dual effect on the IGABA increasing the current in the control solution and decreasing the stimulatory effect of ALLO.

Two Mechanisms That Raise Free Intracellular Calcium in Rat Hippocampal Neurons During Hypoosmotic and Low NaCl Treatment

2000 ◽  
Vol 83 (1) ◽  
pp. 81-89 ◽  
Author(s):  
Aren J. Borgdorff ◽  
George G. Somjen ◽  
Wytse J. Wadman
Keyword(s):  
Synaptic Transmission ◽  
Intracellular Calcium ◽  
Hippocampal Neurons ◽  
Pyramidal Neurons ◽  
Hippocampal Slices ◽  
Cell Swelling ◽  
Tissue Slices ◽  
Extracellular Medium ◽  
Calcium Activity ◽  
Hippocampal Pyramidal Neurons

Previous studies have shown that exposing hippocampal slices to low osmolarity (πo) or to low extracellular NaCl concentration ([NaCl]o) enhances synaptic transmission and also causes interstitial calcium ([Ca2+]o) to decrease. Reduction of [Ca2+]o suggests cellular uptake and could explain the potentiation of synaptic transmission. We measured intracellular calcium activity ([Ca2+]i) using fluorescent indicator dyes. In CA1 hippocampal pyramidal neurons in tissue slices, lowering πo by ∼70 mOsm caused “resting” [Ca2+]i as well as synaptically or directly stimulated transient increases of calcium activity (Δ[Ca2+]i) to transiently decrease and then to increase. In dissociated cells, lowering πo by ∼70 mOsm caused [Ca2+]i to almost double on average from 83 to 155 nM. The increase of [Ca2+]i was not significantly correlated with hypotonic cell swelling. Isoosmotic (mannitol- or sucrose-substituted) lowering of [NaCl]o, which did not cause cell swelling, also raised [Ca2+]i. Substituting NaCl with choline-Cl or Na-methyl-sulfate did not affect [Ca2+]i. In neurons bathed in calcium-free medium, lowering πo caused a milder increase of [Ca2+]i, which was correlated with cell swelling, but in the absence of external Ca2+, isotonic lowering of [NaCl]o triggered only a brief, transient response. We conclude that decrease of extracellular ionic strength (i.e., in both low πo and low [NaCl]o) causes a net influx of Ca2+ from the extracellular medium whereas cell swelling, or the increase in membrane tension, is a signal for the release of Ca2+ from intracellular stores.

scholarly journals Aged xCT-Deficient Mice Are Less Susceptible for Lactacystin-, but Not 1-Methyl-4-Phenyl-1,2,3,6- Tetrahydropyridine-, Induced Degeneration of the Nigrostriatal Pathway

2021 ◽  
Vol 15 ◽  
Author(s):  
Eduard Bentea ◽  
Laura De Pauw ◽  
Lise Verbruggen ◽  
Lila C. Winfrey ◽  
Lauren Deneyer ◽  
...  
Keyword(s):  
Dopaminergic Neurons ◽  
Proteasome Inhibition ◽  
Cell Loss ◽  
Redox Balance ◽  
Nigrostriatal Pathway ◽  
Knock Out ◽  
Aged Mice ◽  
Adult Mice ◽  
Age Related ◽  
Nigrostriatal Degeneration

The astrocytic cystine/glutamate antiporter system xc– (with xCT as the specific subunit) imports cystine in exchange for glutamate and has been shown to interact with multiple pathways in the brain that are dysregulated in age-related neurological disorders, including glutamate homeostasis, redox balance, and neuroinflammation. In the current study, we investigated the effect of genetic xCT deletion on lactacystin (LAC)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced degeneration of the nigrostriatal pathway, as models for Parkinson’s disease (PD). Dopaminergic neurons of adult xCT knock-out mice (xCT–/–) demonstrated an equal susceptibility to intranigral injection of the proteasome inhibitor LAC, as their wild-type (xCT+/+) littermates. Contrary to adult mice, aged xCT–/– mice showed a significant decrease in LAC-induced degeneration of nigral dopaminergic neurons, depletion of striatal dopamine (DA) and neuroinflammatory reaction, compared to age-matched xCT+/+ littermates. Given this age-related protection, we further investigated the sensitivity of aged xCT–/– mice to chronic and progressive MPTP treatment. However, in accordance with our previous observations in adult mice (Bentea et al., 2015a), xCT deletion did not confer protection against MPTP-induced nigrostriatal degeneration in aged mice. We observed an increased loss of nigral dopaminergic neurons, but equal striatal DA denervation, in MPTP-treated aged xCT–/– mice when compared to age-matched xCT+/+ littermates. To conclude, we reveal age-related protection against proteasome inhibition-induced nigrostriatal degeneration in xCT–/– mice, while xCT deletion failed to protect nigral dopaminergic neurons of aged mice against MPTP-induced toxicity. Our findings thereby provide new insights into the role of system xc– in mechanisms of dopaminergic cell loss and its interaction with aging.

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