scholarly journals Mutant Cx30-A88V mice exhibit hydrocephaly and sex-dependent behavioral abnormalities, implicating a functional role for Cx30 in the brain

2021 ◽  
Vol 14 (1) ◽  
pp. dmm046235
Author(s):  
Nicole M. Novielli-Kuntz ◽  
Eric R. Press ◽  
Kevin Barr ◽  
Marco A. M. Prado ◽  
Dale W. Laird
Keyword(s):  
Connexin 43 ◽  
Cell Layer ◽  
Ependymal Cell ◽  
Morphological Changes ◽  
Abnormal Behavior ◽  
Brain Morphology ◽  
Ependymal Cells ◽  
Male And Female ◽  
Female Mice ◽  
The Brain

ABSTRACTConnexin 30 (Cx30; also known as Gjb6 when referring to the mouse gene) is expressed in ependymal cells of the brain ventricles, in leptomeningeal cells and in astrocytes rich in connexin 43 (Cx43), leading us to question whether patients harboring GJB6 mutations exhibit any brain anomalies. Here, we used mice harboring the human disease-associated A88V Cx30 mutation to address this gap in knowledge. Brain Cx30 levels were lower in male and female Cx30A88V/A88V mice compared with Cx30A88V/+ and Cx30+/+ mice, whereas Cx43 levels were lower only in female Cx30 mutant mice. Characterization of brain morphology revealed a disrupted ependymal cell layer, significant hydrocephalus and enlarged ventricles in 3- to 6-month-old adult male and female Cx30A88V/A88V mice compared with Cx30A88V/+ or Cx30+/+ sex-matched littermate mice. To determine the functional significance of these molecular and morphological changes, we investigated a number of behavioral activities in these mice. Interestingly, only female Cx30A88V/A88V mice exhibited abnormal behavior compared with all other groups. Cx30A88V/A88V female mice demonstrated increased locomotor and exploratory activity in both the open field and the elevated plus maze. They also exhibited dramatically reduced ability to learn the location of the escape platform during Morris water maze training, although they were able to swim as well as other genotypes. Our findings suggest that the homozygous A88V mutation in Cx30 causes major morphological changes in the brain of aging mice, possibly attributable to an abnormal ependymal cell layer. Remarkably, these changes had a more pronounced consequence for cognitive function in female mice, which is likely to be linked to the dysregulation of both Cx30 and Cx43 levels in the brain.

scholarly journals Involvement of NMDA receptors containing the GluN2C subunit in the psychotomimetic and antidepressant-like effects of ketamine

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Mireia Tarrés-Gatius ◽  
Lluís Miquel-Rio ◽  
Leticia Campa ◽  
Francesc Artigas ◽  
Anna Castañé
Keyword(s):  
Motor Coordination ◽  
Sensory Information ◽  
Wild Type ◽  
Thalamic Nuclei ◽  
Treatment Resistant ◽  
Cortical Networks ◽  
Male And Female ◽  
Female Mice ◽  
Antidepressant Effects ◽  
The Brain

AbstractAcute ketamine administration evokes rapid and sustained antidepressant effects in treatment-resistant patients. However, ketamine also produces transient perceptual disturbances similarly to those evoked by other non-competitive NMDA-R antagonists like phencyclidine (PCP). Although the brain networks involved in both ketamine actions are not fully understood, PCP and ketamine activate thalamo-cortical networks after NMDA-R blockade in GABAergic neurons of the reticular thalamic nucleus (RtN). Given the involvement of thalamo-cortical networks in processing sensory information, these networks may underlie psychotomimetic action. Since the GluN2C subunit is densely expressed in the thalamus, including the RtN, we examined the dependence of psychotomimetic and antidepressant-like actions of ketamine on the presence of GluN2C subunits, using wild-type and GluN2C knockout (GluN2CKO) mice. Likewise, since few studies have investigated ketamine’s effects in females, we used mice of both sexes. GluN2C deletion dramatically reduced stereotyped (circling) behavior induced by ketamine in male and female mice, while the antidepressant-like effect was fully preserved in both genotypes and sexes. Despite ketamine appeared to induce similar effects in both sexes, some neurobiological differences were observed between male and female mice regarding c-fos expression in thalamic nuclei and cerebellum, and glutamate surge in prefrontal cortex. In conclusion, the GluN2C subunit may discriminate between antidepressant-like and psychotomimetic actions of ketamine. Further, the abundant presence of GluN2C subunits in the cerebellum and the improved motor coordination of GluN2CKO mice after ketamine treatment suggest the involvement of cerebellar NMDA-Rs in some behavioral actions of ketamine.

scholarly journals Streptococcus pneumoniae-Induced Inhibition of Rat Ependymal Cilia Is Attenuated by Antipneumolysin Antibody

2004 ◽  
Vol 72 (11) ◽  
pp. 6694-6698 ◽  
Author(s):  
Robert A. Hirst ◽  
Bashir J. Mohammed ◽  
Timothy J. Mitchell ◽  
Peter W. Andrew ◽  
Christopher O'Callaghan
Keyword(s):  
Streptococcus Pneumoniae ◽  
Therapeutic Potential ◽  
Ependymal Cell ◽  
Ex Vivo ◽  
Beat Frequency ◽  
Ciliary Beat Frequency ◽  
Ependymal Cells ◽  
Wild Type ◽  
Ependymal Cilia ◽  
The Brain

ABSTRACT Ciliated ependymal cells line the ventricular surfaces and aqueducts of the brain. In ex vivo experiments, pneumolysin caused rapid inhibition of the ependymal ciliary beat frequency and caused ependymal cell disruption. Wild-type pneumococci and pneumococci deficient in pneumolysin caused ciliary slowing, but penicillin lysis of wild-type, not pneumolysin-deficient, pneumococci increased the extent of ciliary inhibition. This effect was abolished by antipneumolysin antibody. Ependymal ciliary stasis by purified pneumolysin was also blocked by the addition of antipneumolysin monoclonal antibodies. These data show that antibiotic lysis of Streptococcus pneumoniae can be detrimental to the ciliated ependyma and that antipneumolysin antibody may have a therapeutic potential.

scholarly journals Leptin pharmacokinetics in male mice

2017 ◽  
Vol 6 (1) ◽  
pp. 20-26 ◽  
Author(s):  
Robert A Hart ◽  
Robin C Dobos ◽  
Linda L Agnew ◽  
Neil A Smart ◽  
James R McFarlane
Keyword(s):  
Digestive Tract ◽  
Time Course ◽  
Normal Male ◽  
Male Mice ◽  
Male And Female ◽  
Female Mice ◽  
Males And Females ◽  
High Degree ◽  
The Brain ◽  
Major Target

Pharmacokinetics of leptin in mammals has not been studied in detail and only one study has examined more than one time point in non-mutant mice and this was in a female mice. This is the first study to describe leptin distribution over a detailed time course in normal male mice. A physiologic dose (12 ng) of radiolabelled leptin was injected into adult male mice via the lateral tail vein and tissues were dissected out and measured for radioactivity over a time course of up to two hours. Major targets were the digestive tract, kidneys, skin and lungs. The brain was not a major target, and 0.15% of the total dose was recovered from the brain 5 min after administration. Major differences appear to exist in the distribution of leptin between the male and female mice, indicating a high degree of sexual dimorphism. Although the half-lives were similar between male and female mice, almost twice the proportion of leptin was recovered from the digestive tract of male mice in comparison to that reported previously for females. This would seem to indicate a major difference in leptin distribution and possibly function between males and females.

scholarly journals Single Cell Transcriptomics of Ependymal Cells Across Age, Region and Species Reveals Cilia-Related and Metal Ion Regulatory Roles as Major Conserved Ependymal Cell Functions

2021 ◽  
Vol 15 ◽  
Author(s):  
Adam MacDonald ◽  
Brianna Lu ◽  
Maxime Caron ◽  
Nina Caporicci-Dinucci ◽  
Dale Hatrock ◽  
...  
Keyword(s):  
Single Cell ◽  
Spinal Canal ◽  
Metal Ion ◽  
Ependymal Cell ◽  
Critical Role ◽  
Ependymal Cells ◽  
Cellular Transport ◽  
Cell Functions ◽  
Metal Ion Homeostasis ◽  
The Brain

Ependymal cells are ciliated-epithelial glial cells that develop from radial glia along the surface of the ventricles of the brain and the spinal canal. They play a critical role in cerebrospinal fluid (CSF) homeostasis, brain metabolism, and the clearance of waste from the brain. These cells have been implicated in disease across the lifespan including developmental disorders, cancer, and neurodegenerative disease. Despite this, ependymal cells remain largely understudied. Using single-cell RNA sequencing data extracted from publicly available datasets, we make key findings regarding the remarkable conservation of ependymal cell gene signatures across age, region, and species. Through this unbiased analysis, we have discovered that one of the most overrepresented ependymal cell functions that we observed relates to a critically understudied role in metal ion homeostasis. Our analysis also revealed distinct subtypes and states of ependymal cells across regions and ages of the nervous system. For example, neonatal ependymal cells maintained a gene signature consistent with developmental processes such as determination of left/right symmetry; while adult ventricular ependymal cells, not spinal canal ependymal cells, appeared to express genes involved in regulating cellular transport and inflammation. Together, these findings highlight underappreciated functions of ependymal cells, which will be important to investigate in order to better understand these cells in health and disease.

scholarly journals Id4 is required for normal ependymal cell development

2021 ◽  
Author(s):  
Brenda Rocamonde ◽  
Vicente Herranz-Pérez ◽  
Jose-Manuel Garcia-Verdugo ◽  
Emmanuelle Huillard
Keyword(s):  
Radial Glia ◽  
Ependymal Cell ◽  
Cell Number ◽  
Cell Development ◽  
Ependymal Cells ◽  
Cerebrospinal Fluid Flow ◽  
Multiciliated Cells ◽  
Brain And Spinal Cord ◽  
The Brain

AbstractEpendymal cells are radial glia-derived multiciliated cells lining the lateral ventricles of the brain and spinal cord. Correct development and coordinated cilia beating is essential for proper cerebrospinal fluid flow (CSF) and neurogenesis modulation. Dysfunctions of ependymal cells were associated with transcription factor deregulation. Here we provide evidence that the transcriptional regulator Id4 is involved in ependymal cell development and maturation. We observed that Id4-deficient mice display altered ependymal cytoarchitecture, decreased ependymal cell number, altered CSF flow and enlarged ventricles. Our findings open the way for a potential role of Id4 in ependymal cell development and/or motor cilia function.

scholarly journals Effects of L-Dopa, SKF-38393, and Quinpirole on exploratory, anxiety- and depressive-like behaviors in pubertal female and male mice

2021 ◽  
Author(s):  
Muiara A. Moraes ◽  
Laila Blanc Arabe ◽  
Bruna L. Resende ◽  
Beatriz C. Codo ◽  
Ana Luiza A. L. Reis ◽  
...  
Keyword(s):  
Dopamine Receptor ◽  
Receptor Agonist ◽  
Time Window ◽  
Skf 38393 ◽  
Abnormal Behavior ◽  
Dopamine Receptor Agonist ◽  
Male And Female ◽  
Dopaminergic Tone ◽  
In The Beginning ◽  
The Brain

Adolescence is a phase of substantial changes in the brain, characterized by maturational remodeling of many systems. This remodeling allows functional plasticity to adapt in a changing environment but turns this period into a neurodevelopmental vulnerable window. The dopaminergic system is under morphological and physiological changes during this phase. The disruption of its balance can lead to molecular variation and abnormal behavior - representing a risk factor for neuropsychiatric disorders. In the present study, we investigated if changes in the dopaminergic tone alter mice behavior in a receptor and sex-specific manner, specifically in the beginning of puberty period. We administered L-Dopa, SKF-38393 (D1 dopamine receptor agonist) and Quinpirole (D2 dopamine receptor agonist) and tested male and female mice motor, anxiety- and depressive-like behavior. While females displayed an impaired exploratory drive, males presented an intense depressive-like response. Our results provide insights into the function of dopaminergic development in adolescent behavior and highlight the importance of studies in this time window with male and female subjects.

scholarly journals ID4 Is Required for Normal Ependymal Cell Development

2021 ◽  
Vol 15 ◽  
Author(s):  
Brenda Rocamonde ◽  
Vicente Herranz-Pérez ◽  
Jose Manuel Garcia-Verdugo ◽  
Emmanuelle Huillard
Keyword(s):  
Radial Glia ◽  
Ependymal Cell ◽  
Cell Number ◽  
Cell Development ◽  
Ependymal Cells ◽  
Multiciliated Cells ◽  
Delayed Maturation ◽  
Brain And Spinal Cord ◽  
The Brain

Ependymal cells are radial glia-derived multiciliated cells lining the lateral ventricles of the brain and spinal cord. Correct development and coordinated cilia beating is essential for proper cerebrospinal fluid (CSF) flow and neurogenesis modulation. Dysfunctions of ependymal cells were associated with transcription factor deregulation. Here we provide evidence that the transcriptional regulator ID4 is involved in ependymal cell development and maturation. We observed that Id4-deficient mice display altered ventricular cell cytoarchitecture, decreased ependymal cell number and enlarged ventricles. In addition, absence of ID4 during embryonic development resulted in decreased ependymal cell number and delayed maturation. Our findings open the way for a potential role of ID4 in ependymal cell development and motor cilia function.

scholarly journals Iba1+ cell density and morphology classification at postnatal day 10 in four hippocampal subregions of female and male C57BL/6J mice

2021 ◽  
Author(s):  
Danielle Guez-Barber ◽  
Max Wragan ◽  
Dana Raphael ◽  
Haley M. Phillips ◽  
Kira Lu ◽  
...  
Keyword(s):  
Sex Differences ◽  
Cell Density ◽  
Female Rats ◽  
Male Rats ◽  
Lower Percentage ◽  
Male Mice ◽  
Male And Female ◽  
Female Mice ◽  
Mouse Hippocampus ◽  
The Brain

Microglia maintain normal brain function and support the brain′s response to disease and injury. The hippocampus is an area of focus for microglial study due to its central role in numerous behavioral and cognitive functions. Interestingly, microglia and related cells in the hippocampus and throughout the brain are distinct in male vs. female rodents, even in early life. Indeed, postnatal day (P)-dependent sex differences in number, density, and morphology of microglia-like cells have been reported in certain hippocampal subregions. For example, P3 female mice have more phagocytic microglia in dentate gyrus (DG) molecular layer (Mol) and CA1-3 stratum oriens (SO) regions vs. male mice, while P8 — but not P15 — male rats have more volume immunoreactive for markers of microglia-like cells (Iba1 and CD68) in the CA1 stratum radiatum (SR) vs. female rats. In the mouse, P10 is roughly equivalent to human term gestation, making it a common time point to study for many translationally-relevant neurobiological processes. However, sex differences in hippocampal microglia have not been examined in the P10 mouse hippocampus. In addition, key subregions of the hippocampus — CA3 SR, DG hilus — have not yet been assessed for sex differences in microglia. To address these knowledge gaps, we quantified Iba1+ cell densities and classified Iba1+ cell morphology in P10 male and female C57BL/6J mice. Four subregions in the bilateral anterior hippocampus were analyzed in 40-μm coronal sections: DG Mol (Mol), DG Hilus, CA1 SR and stratum lacunosum moleculare (CA1), and CA3 SR and stratum lucidum (CA3). Light microscope images (40x) were analyzed offline for Iba1+ cell density and morphology by an observer blind to sex. The morphology of each Iba1+ cell was used to place cells into one of four previously-published categories: Round or ameboid (round-ish soma, no processes), Stout (round-ish soma, short process), Thick (irregular soma with few, thick processes), or Thin (irregular soma with multiple thin processes). Analysis of Iba1+ cell density shows no difference between male and female mice in Mol, Hilus, CA3, or CA1 (male n=6, female n=7). However, morphology classification shows a sex-dependent difference in the Mol and Hilus, with female mice having a greater percentage of Thick Iba1+ cells vs. male mice (Mol, Hilus), and a lower percentage of Thin Iba1+ cells vs. male mice (Mol). With our analysis, it is unclear whether this greater percentage of thick and lower percentage of thin Iba1+ cells in the female vs. male hippocampus means Iba1+ microglia in female mice are ″younger″ or ″more active″ than those in male mice. However, these data are important as they reveal sex differences in Iba1+ microglia in the P10 mouse hippocampus. We discuss these results in the context of the large literature on sex differences in rodent microglia in the early postnatal period.

Early gender differences in the redox status of the brain mitochondria with age: effects of melatonin therapy

2013 ◽  
Vol 16 (2) ◽  
Author(s):  
Germaine Escames ◽  
María E. Díaz-Casado ◽  
Carolina Doerrier ◽  
Marta Luna-Sánchez ◽  
Luis C. López ◽  
...  
Keyword(s):  
Gender Differences ◽  
Mitochondrial Dysfunction ◽  
Nitrosative Stress ◽  
Brain Mitochondria ◽  
Male And Female ◽  
Atp Production ◽  
Female Mice ◽  
Stress Markers ◽  
Melatonin Administration ◽  
The Brain

AbstractMitochondrial dysfunction and oxidative/nitrosative stress are common features of senescence, and they explain some of the pathophysiological events during aging. In different animal models of aging, the existence of oxidative stress, inflammation, and mitochondrial dysfunction has been reported. There is no information, however, regarding the age when these symptoms begin and if they account for gender differences in aging. Here we analyzed oxidative/nitrosative stress markers and bioenergetics in the brain mitochondria of normal mice during the first 10 months of life, looking for early signs of senescence. Male and female mice were treated with vehicle or melatonin during the first 9 months of life, starting at weaning. Mice were sacrificed at 5 and 10 months of life, and pure brain mitochondria were prepared and assayed for respiratory chain activity, ATP production, and oxidative/nitrosative stress status. The results showed that the brain mitochondria from male mice have a better glutathione cycle than female mice, whereas female mice have higher electron transport chain activity and ATP production at 5 months old. Five months later, however, oxidative/nitrosative stress markers increased in both male and female mice, thus eliminating the differences between the genders. More importantly, these changes were prevented by chronic melatonin administration, which also restored the gender differences found in 5-month-old mice. Thus, melatonin administration as a single therapy can maintain the full function of the brain mitochondria during the early events of aging, a finding that has important consequences in the pathophysiology of brain senescence.

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