scholarly journals Serotonin, norepinephrine and acetylcholine differentially affect astrocytic potassium clearance to modulate somatosensory signaling in male mice

2019 ◽  
Author(s):  
Caitlin A. Wotton ◽  
Cassidy D. Cross ◽  
Lane K. Bekar
Keyword(s):  
Network Activity ◽  
Extracellular Potassium ◽  
Male Mice ◽  
Somatosensory Stimulation ◽  
Differential Effects ◽  
Network Function ◽  
Potassium Regulation ◽  
Gated Channel ◽  
Potassium Clearance ◽  
The Impact

AbstractChanges in extracellular potassium ([K+]e) modulate neuronal networks via changes in membrane potential, voltage-gated channel activity and alteration of transmission at the synapse. Given the limited extracellular space in the CNS, potassium clearance is crucial. As activity-induced potassium transients are rapidly managed by astrocytic Kir4.1 and astrocyte-specific Na+/K+-ATPase (NKA), any neurotransmitter/neuromodulator that can regulate their function may have indirect influence on network activity. Neuromodulators differentially affect cortical/thalamic networks to align sensory processing with differing behavioral states. Given serotonin (5HT), norepinephrine (NE), and acetylcholine (ACh) differentially affect spike frequency adaptation and signal fidelity (“signal-to-noise”) in somatosensory cortex, we hypothesize that [K+]e may be differentially regulated by the different neuromodulators to exert their individual effects on network function. This study aimed to compare effects of individually applied 5HT, NE, and ACh on regulating [K+]e in connection to effects on cortical evoked response amplitude and adaptation in male mice. Using extracellular field and K+ ion-selective recordings of somatosensory stimulation, we found that differential effects of 5HT, NE, and ACh on [K+]e regulation mirrored differential effects on amplitude and adaptation. 5HT effects on transient K+ recovery, adaptation and field post-synaptic potential amplitude were disrupted by barium (200 µM), whereas NE and ACh effects were disrupted by ouabain (1 µM) or iodoacetate (100 µM). Considering the impact [K+]e can have on many network functions; it seems highly efficient that neuromodulators regulate [K+]e to exert their many effects. This study provides functional significance for astrocyte-mediated buffering of [K+]e in neuromodulator-mediated shaping of cortical network activity.Significance statementWe demonstrate that the neuromodulators serotonin, norepinephrine, and acetylcholine all have distinct effects on astrocyte-mediated extracellular potassium regulation and that these differential actions are associated with the different effects of the neuromodulators on cortical networks. By affecting astrocytic potassium regulation, long-range neuromodulatory networks can rapidly and efficiently affect broad areas of the brain. Given that neuromodulatory networks are at the core of our behavioral state and determine how we interact with our environment, these studies highlight the importance of basic astrocyte function in general cognition and psychiatric disorders.

scholarly journals Neuromodulation of Astrocytic K+ Clearance

2021 ◽  
Vol 22 (5) ◽  
pp. 2520
Author(s):  
Alba Bellot-Saez ◽  
Rebecca Stevenson ◽  
Orsolya Kékesi ◽  
Evgeniia Samokhina ◽  
Yuval Ben-Abu ◽  
...  
Keyword(s):  
Oscillatory Behavior ◽  
Network Activity ◽  
Oscillatory Activity ◽  
Extracellular Potassium ◽  
Uptake Mechanism ◽  
Kir Channels ◽  
Neuronal Network Activity ◽  
Clearance Process ◽  
Spatial Buffering ◽  
The Impact

Potassium homeostasis is fundamental for brain function. Therefore, effective removal of excessive K+ from the synaptic cleft during neuronal activity is paramount. Astrocytes play a key role in K+ clearance from the extracellular milieu using various mechanisms, including uptake via Kir channels and the Na+-K+ ATPase, and spatial buffering through the astrocytic gap-junction coupled network. Recently we showed that alterations in the concentrations of extracellular potassium ([K+]o) or impairments of the astrocytic clearance mechanism affect the resonance and oscillatory behavior of both the individual and networks of neurons. These results indicate that astrocytes have the potential to modulate neuronal network activity, however, the cellular effectors that may affect the astrocytic K+ clearance process are still unknown. In this study, we have investigated the impact of neuromodulators, which are known to mediate changes in network oscillatory behavior, on the astrocytic clearance process. Our results suggest that while some neuromodulators (5-HT; NA) might affect astrocytic spatial buffering via gap-junctions, others (DA; Histamine) primarily affect the uptake mechanism via Kir channels. These results suggest that neuromodulators can affect network oscillatory activity through parallel activation of both neurons and astrocytes, establishing a synergistic mechanism to maximize the synchronous network activity.

scholarly journals Altered network properties in C9ORF72 repeat expansion cortical neurons are due to synaptic dysfunction

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Emma M. Perkins ◽  
Karen Burr ◽  
Poulomi Banerjee ◽  
Arpan R. Mehta ◽  
Owen Dando ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Synaptic Vesicle ◽  
Cortical Neurons ◽  
Electrode Array ◽  
Repeat Expansion ◽  
Cortical Network ◽  
Synaptic Function ◽  
Network Activity ◽  
Cortical Function ◽  
Network Function

Abstract Background Physiological disturbances in cortical network excitability and plasticity are established and widespread in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients, including those harbouring the C9ORF72 repeat expansion (C9ORF72RE) mutation – the most common genetic impairment causal to ALS and FTD. Noting that perturbations in cortical function are evidenced pre-symptomatically, and that the cortex is associated with widespread pathology, cortical dysfunction is thought to be an early driver of neurodegenerative disease progression. However, our understanding of how altered network function manifests at the cellular and molecular level is not clear. Methods To address this we have generated cortical neurons from patient-derived iPSCs harbouring C9ORF72RE mutations, as well as from their isogenic expansion-corrected controls. We have established a model of network activity in these neurons using multi-electrode array electrophysiology. We have then mechanistically examined the physiological processes underpinning network dysfunction using a combination of patch-clamp electrophysiology, immunocytochemistry, pharmacology and transcriptomic profiling. Results We find that C9ORF72RE causes elevated network burst activity, associated with enhanced synaptic input, yet lower burst duration, attributable to impaired pre-synaptic vesicle dynamics. We also show that the C9ORF72RE is associated with impaired synaptic plasticity. Moreover, RNA-seq analysis revealed dysregulated molecular pathways impacting on synaptic function. All molecular, cellular and network deficits are rescued by CRISPR/Cas9 correction of C9ORF72RE. Our study provides a mechanistic view of the early dysregulated processes that underpin cortical network dysfunction in ALS-FTD. Conclusion These findings suggest synaptic pathophysiology is widespread in ALS-FTD and has an early and fundamental role in driving altered network function that is thought to contribute to neurodegenerative processes in these patients. The overall importance is the identification of previously unidentified defects in pre and postsynaptic compartments affecting synaptic plasticity, synaptic vesicle stores, and network propagation, which directly impact upon cortical function.

Effect of Common Anesthetics on Dendritic Properties in Layer 5 Neocortical Pyramidal Neurons

2008 ◽  
Vol 99 (3) ◽  
pp. 1394-1407 ◽  
Author(s):  
Sarah Potez ◽  
Matthew E. Larkum
Keyword(s):  
High Frequency ◽  
Pyramidal Neurons ◽  
Animal Experiments ◽  
Apical Dendrite ◽  
Network Activity ◽  
Calcium Spikes ◽  
Firing Properties ◽  
The Impact

Understanding the impact of active dendritic properties on network activity in vivo has so far been restricted to studies in anesthetized animals. However, to date no study has been made to determine the direct effect of the anesthetics themselves on dendritic properties. Here, we investigated the effects of three types of anesthetics commonly used for animal experiments (urethane, pentobarbital and ketamine/xylazine). We investigated the generation of calcium spikes, the propagation of action potentials (APs) along the apical dendrite and the somatic firing properties in the presence of anesthetics in vitro using dual somatodendritic whole cell recordings. Calcium spikes were evoked with dendritic current injection and high-frequency trains of APs at the soma. Surprisingly, we found that the direct actions of anesthetics on calcium spikes were very different. Two anesthetics (urethane and pentobarbital) suppressed dendritic calcium spikes in vitro, whereas a mixture of ketamine and xylazine enhanced them. Propagation of spikes along the dendrite was not significantly affected by any of the anesthetics but there were various changes in somatic firing properties that were highly dependent on the anesthetic. Last, we examined the effects of anesthetics on calcium spike initiation and duration in vivo using high-frequency trains of APs generated at the cell body. We found the same anesthetic-dependent direct effects in addition to an overall reduction in dendritic excitability in anesthetized rats with all three anesthetics compared with the slice preparation.

Abstract 390: The Absence of Abcg5 Abcg8 Reveals a Sexually Dimorphic Adaption to Impaired Biliary Cholesterol Secretion

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Jianing Li ◽  
Ailing Ji ◽  
Ryan E Temel ◽  
Deneys R van der Westhuyzen ◽  
Gregory A Graf
Keyword(s):  
Alternative Pathway ◽  
Male Mice ◽  
Biliary Cholesterol ◽  
Female Mice ◽  
Cholesterol Excretion ◽  
Biliary Cholesterol Secretion ◽  
Cholesterol Secretion ◽  
The Impact ◽  
Sterol Excretion ◽  
Secretion Rates

Objective: The ABCG5 ABCG8 (G5G8) sterol transporter is the primary mechanism for biliary cholesterol secretion, but mice maintain fecal sterol excretion in its absence. The mechanism by which mice maintain sterol excretion in the absence of this pathway is not known. Transintestinal cholesterol excretion (TICE) is an alternative pathway to hepatobiliary secretion. We investigated the impact of G5G8 deficiency on TICE in the absence of Sitosterolemia. Methods and Results: We compared both hepatobiliary and transintestinal cholesterol excretion rates in wild-type (WT) and G5G8 deficient mice of both sexes. WT and G5G8 were maintained on a plant-sterol free diet from the time of weaning to prevent the development of secondary phenotypes associated with Sitosterolemia. Biliary and intestinal cholesterol secretion rates were determined by biliary diversion with simultaneous perfusion of the proximal 10 cm of the small bowel. Among WT mice, biliary cholesterol secretion was greater in female mice compared to males. Conversely, male mice exhibited greater rates of TICE than females. As expected, WT mice had higher biliary cholesterol secretion rates than their G5G8 deficient littermates. However, the decline in biliary cholesterol secretion was far less in male mice compared to females in the absence of G5G8. In female mice, the absence of G5G8 resulted in a two-fold increase in TICE, whereas males were unaffected. Conclusion: Female mice are more dependent upon the biliary pathway for cholesterol excretion, whereas males are more dependent upon TICE. G5G8 independent pathways are present for both biliary and intestinal cholesterol secretion. Female and male mice differ in their adaptation to G5G8 deficiency in order to maintain fecal sterol excretion.

scholarly journals The Impact of Time-Restricted Feeding on Exercise-Induced Immune Parameters in C57BL/6 Male Mice

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1541-1541
Author(s):  
Marie van der Merwe ◽  
Martina Faietti ◽  
Richard Bloomer ◽  
Melissa Puppa ◽  
Aaron Persinger ◽  
...  
Keyword(s):  
Immune Cell ◽  
Control Group ◽  
Intermittent Fasting ◽  
Restricted Feeding ◽  
Male Mice ◽  
Immune Parameters ◽  
Tnf Α ◽  
Exercise Induced ◽  
Access To Food ◽  
The Impact

Abstract Objectives Food intake and exercise are considered modulators of the immune system. Specifically, intermittent fasting protocols have been demonstrated to reduce inflammation and alter cytokine responses. The objective of the current study was to determine if a form of intermittent fasting known as time-restricted feeding (TRF) would alter immune parameters in response to exercise. Methods 8-week-old C57BL/6 male mice were divided into three groups based on feeding schedule; group one had access to food ad libitum (Control) and groups two and three had access to food in a time restricted manner. Access was allowed for six hours per day either immediately after running (TRF-imm) or six hours after running (TRF-del). Mice ran on a treadmill for 1 hour, 5 days per week for eight weeks. Diet consisted of 21% protein, 16% fat and 64% carbohydrate. Weight, glucose and ketone levels, and immune populations were analyzed. Systemic IL-6 and TNF-α levels were measured before and after running. In a subpopulation, cytokine response to lipopolysaccharides (LPS) was also monitored. Results All mice gained weight during the eight-week intervention, but TRF-imm gained significantly less weight than Control (P = 0.02). No differences were detected in glucose levels. The ketone body β-hydroxybutyrate (BHB) was significantly higher at week eight in TRF groups (P ≤ 0.03) but running induced BHB in all groups to approximately 1 mM. Running reduced the blood lymphocytes levels (P < 0.05), with a concomitant increase of granulocytes (P < 0.05) in all groups. There was a small increase in monocytes only in the Control group (P = 0.017). No differences were detected in splenic immune populations, including CD4 and CD8 T cells, and CD11b + cells. Both IL-6 and TNF-α levels were low in all groups before exercise; however, post exercise IL-6 was increased, but not to the same extend in all groups. The IL-6 response was blunted in the TRF groups. The reduced levels of IL-6 was not due to loss of immune function, as both IL-6 and TNF-α were readily induced by exposure of mice to LPS. Conclusions Time-restricted feeding protocols did not induce differences in immune cell composition in blood or spleen but resulted in attenuated exercise-induced IL-6 levels. Funding Sources University of Memphis, School of Health Studies.

scholarly journals Impact of sex, androgens, and prostate size on C57BL/6J mouse urinary physiology: urethral histology

2020 ◽  
Vol 318 (3) ◽  
pp. F617-F627
Author(s):  
Hannah Ruetten ◽  
Kyle A. Wegner ◽  
Conner L. Kennedy ◽  
Anne Turco ◽  
Helen L. Zhang ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Cell Count ◽  
National Institutes Of Health ◽  
Male Mice ◽  
Male And Female ◽  
Future Studies ◽  
Biological Variable ◽  
Prostate Size ◽  
Hematoxylin And Eosin ◽  
The Impact

The National Institutes of Health leveled new focus on sex as a biological variable with the goal of understanding sex-specific differences in health and physiology. We previously published a functional assessment of the impact of sex, androgens, and prostate size on C57BL/6J mouse urinary physiology (Ruetten H, Wegner KA, Zhang HL, Wang P, Sandhu J, Sandhu S, Mueller B, Wang Z, Macoska J, Peterson RE, Bjorling DE, Ricke WA, Marker PC, Vezina CM. Am J Physiol Renal Physiol 317: F996–F1009, 2019). Here, we measured and compared five characteristics of urethral histology (urethral lumen diameter and area, epithelial cell count, epithelial and rhabdosphincter thickness, epithelial cell area, and total urethral area) in male and female 9-wk-old C57BL/6J mice using hematoxylin and eosin staining. We also compared male mice with castrated male mice, male and female mice treated with the steroid 5α-reductase inhibitor finasteride or testosterone, or male mice harboring alleles ( Pbsn4cre/+; R26RDta/+) that reduce prostate lobe mass. The three methods used to reduce prostate mass (castration, finasteride, and Pbsn4cre/+; R26RDta/+) changed urethral histology, but none feminized male urethral histology (increased urethral epithelial area). Exogenous testosterone caused increased epithelial cell count in intact females but did not masculinize female urethral histology (decrease epithelial area). Our results lay a critical foundation for future studies as we begin to parse out the influence of hormones and cellular morphology on male and female urinary function.

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