Kir 5.1-dependent CO2 /H+ -sensitive currents contribute to astrocyte heterogeneity across brain regions.

Astrocyte heterogeneity is an emerging concept in which astrocytes within or between brain regions show variable morphological and/or gene expression profiles that presumably reflect different functional roles. Recent evidence indicates that retrotrapezoid nucleus (RTN) astrocytes sense changes in tissue CO2/ H+ to regulate respiratory activity; however, mechanism(s) by which they do so remain unclear. Alterations in inward K+ currents represent a potential mechanism by which CO2 /H+ signals may be conveyed to neurons. Here, we use slice electrophysiology in rats of either sex to show that RTN astrocytes intrinsically respond to CO2 /H+ by inhibition of an inward rectifying potassium (Kir ) conductance and depolarization of the membrane, while cortical astrocytes do not exhibit such CO2 /H+ -sensitive properties. Application of Ba2+ mimics the effect of CO2 /H+ on RTN astrocytes as measured by reductions in astrocyte Kir -like currents and increased RTN neuronal firing. These CO2 /H+ -sensitive currents increase developmentally, in parallel to an increased expression in Kir 4.1 and Kir 5.1 in the brainstem. Finally, the involvement of Kir 5.1 in the CO2 /H+ -sensitive current was verified using a Kir5.1 KO rat. These data suggest that Kir inhibition by CO2 /H+ may govern the degree to which astrocytes mediate downstream chemoreceptive signaling events through cell-autonomous mechanisms. These results identify Kir channels as potentially important regional CO2 /H+ sensors early in development, thus expanding our understanding of how astrocyte heterogeneity may uniquely support specific neural circuits and behaviors.

Glial Dysfunction in MeCP2 Deficiency Models: Implications for Rett Syndrome.

Rett syndrome (RTT) is a rare, X-linked neurodevelopmental disorder typically affecting females, resulting in a range of symptoms including autistic features, intellectual impairment, motor deterioration, and autonomic abnormalities. RTT is primarily caused by the genetic mutation of the Mecp2 gene. Initially considered a neuronal disease, recent research shows that glial dysfunction contributes to the RTT disease phenotype. In the following manuscript, we review the evidence regarding glial dysfunction and its effects on disease etiology.

MeCP2 deficiency results in robust Rett-like behavioural and motor deficits in male and female rats.

Since the identification of MECP2 as the causative gene in the majority of Rett Syndrome (RTT) cases, transgenic mouse models have played a critical role in our understanding of this disease. The use of additional mammalian RTT models offers the promise of further elucidating critical early mechanisms of disease as well as providing new avenues for translational studies. We have identified significant abnormalities in growth as well as motor and behavioural function in a novel zinc-finger nuclease model of RTT utilizing both male and female rats throughout development. Male rats lacking MeCP2 (Mecp2ZFN/y) were noticeably symptomatic as early as postnatal day 21, with most dying by postnatal day 55, while females lacking one copy of Mecp2 (Mecp2ZFN/+) displayed a more protracted disease course. Brain weights of Mecp2ZFN/y and Mecp2ZFN/+ rats were significantly reduced by postnatal day 14 and 21, respectively. Early motor and breathing abnormalities were apparent in Mecp2ZFN/y rats, whereas Mecp2ZFN/+ rats displayed functional irregularities later in development. The large size of this species will provide profound advantages in the identification of early disease mechanisms and the development of appropriately timed therapeutics. The current study establishes a foundational basis for the continued utilization of this rat model in future RTT research.

The role of glial-specific Kir4.1 in normal and pathological states of the CNS.

Kir4.1 is an inwardly rectifying K(+) channel expressed exclusively in glial cells in the central nervous system. In glia, Kir4.1 is implicated in several functions including extracellular K(+) homeostasis, maintenance of astrocyte resting membrane potential, cell volume regulation, and facilitation of glutamate uptake. Knockout of Kir4.1 in rodent models leads to severe neurological deficits, including ataxia, seizures, sensorineural deafness, and early postnatal death. Accumulating evidence indicates that Kir4.1 plays an integral role in the central nervous system, prompting many laboratories to study the potential role that Kir4.1 plays in human disease. In this article, we review the growing evidence implicating Kir4.1 in a wide array of neurological disease. Recent literature suggests Kir4.1 dysfunction facilitates neuronal hyperexcitability and may contribute to epilepsy. Genetic screens demonstrate that mutations of KCNJ10, the gene encoding Kir4.1, causes SeSAME/EAST syndrome, which is characterized by early onset seizures, compromised verbal and motor skills, profound cognitive deficits, and salt-wasting. KCNJ10 has also been linked to developmental disorders including autism. Cerebral trauma, ischemia, and inflammation are all associated with decreased astrocytic Kir4.1 current amplitude and astrocytic dysfunction. Additionally, neurodegenerative diseases such as Alzheimer disease and amyotrophic lateral sclerosis demonstrate loss of Kir4.1. This is particularly exciting in the context of Huntington disease, another neurodegenerative disorder in which restoration of Kir4.1 ameliorated motor deficits, decreased medium spiny neuron hyperexcitability, and extended survival in mouse models. Understanding the expression and regulation of Kir4.1 will be critical in determining if this channel can be exploited for therapeutic benefit.

Photodegradation of ibuprofen and four other pharmaceutical pollutants on natural pigments sensitized TiO2 nanoparticles.

Pharmaceuticals and personal care products (PPCPs) in water system have drawn increasing concerns in recent years. TiO2 -based photodegradation has shown great potential as a low-cost and sustainable technology in water treatment, however, can only use the UV light range of solar radiation which makes the system less efficient. Dyes have been studied to improve the TiO2 system light-harvesting range, but studies on environmental friendly natural dyes are rare. In this study, a screening method using UV-Vis spectra analysis was carried out on a group of 22 different tropical natural plants for the potential applications on dye-sensitized TiO2 in PPCP treatment. As a result, Begonia "Martin's Mystery" significantly increased TiO2 photodegradation efficiency toward ibuprofen treatments which is first time reported in literature as our best knowledge. Moreover, the promising discovery of Begonia application in ibuprofen treatment has been successfully applied to warfarin and famotidine treatment. Similar results were expanded to many other Begonia species which indicate that Begonia extracts could be excellent sensitizers for TiO2 -based photodegradation of PPCPs. Our discovery suggested that the screening process may potentially open a brand-new way for future TiO2 photodegradation studies before the complex and time-consuming detailed mechanism studies. PRACTITIONER POINTS.: Natural dyes were screened as sensitizers for TiO2 photodegradation of ibuprofen. Ibuprofen photodegradation efficiency was increased twice using Begonia "Martin's Mystery." The Begonia applications were extended to warfarin, trimethoprim, and famotidine. Promising results were also observed using five other Begonia species.

Chloroplast-to-nucleus retrograde signalling controls intercellular trafficking via plasmodesmata formation.

The signalling pathways that regulate intercellular trafficking via plasmodesmata (PD) remain largely unknown. Analyses of mutants with defects in intercellular trafficking led to the hypothesis that chloroplasts are important for controlling PD, probably by retrograde signalling to the nucleus to regulate expression of genes that influence PD formation and function, an idea encapsulated in the organelle-nucleus-PD signalling (ONPS) hypothesis. ONPS is supported by findings that point to chloroplast redox state as also modulating PD. Here, we have attempted to further elucidate details of ONPS. Through reverse genetics, expression of select nucleus-encoded genes with known or predicted roles in chloroplast gene expression was knocked down, and the effects on intercellular trafficking were then assessed. Silencing most genes resulted in chlorosis, and the expression of several photosynthesis and tetrapyrrole biosynthesis associated nuclear genes was repressed in all silenced plants. PD-mediated intercellular trafficking was changed in the silenced plants, consistent with predictions of the ONPS hypothesis. One striking observation, best exemplified by silencing the PNPase homologues, was that the degree of chlorosis of silenced leaves was not correlated with the capacity for intercellular trafficking. Finally, we measured the distribution of PD in silenced leaves and found that intercellular trafficking was positively correlated with the numbers of PD. Together, these results not only provide further support for ONPS but also point to a genetic mechanism for PD formation, clarifying a longstanding question about PD and intercellular trafficking. This article is part of the theme issue 'Retrograde signalling from endosymbiotic organelles'.