Role of the inward rectifying potassium channel, Kir4.1, in astrocyte physiology and neuronal excitability

During neuronal activity extracellular potassium concentration ([K+]out) becomes elevated and if uncorrected causes neuronal depolarization, hyperexcitability, and seizures. Clearance of K+ from the extracellular space, termed K+ spatial buffering, is considered to be an important function of astrocytes. Results from a number of studies suggest that maintenance of [K+]out by astrocytes is mediated by K+ uptake through Kir4.1 channels. Furthermore, a missense variation in the Kir4.1 gene is linked to seizure susceptibility in mice and humans. To study the role of this channel in astrocyte physiology and neuronal excitability we have generated a conditional knockout (cKO) of Kir4.1 directed to astrocytes via human GFAP promoter, gfa2. Kir4.1 cKO mice die prematurely and display severe ataxia and stress-induced seizures. Histological analysis of Kir4.1 cKO brain and spinal cord revealed white matter vacuolization suggestive of oligodendrocyte pathology. Immunostaining studies confirmed removal of Kir4.1 from cKO astrocytes and oligodendrocytes, indicating that these cell types arise from a common GFAP-expressing precursor. Passive astrocytes in Kir4.1 cKO hippocampus appeared normal in morphology and coupling ability; however, we observed a significant loss of complex astrocytes suggestive of Kir4.1 role in astrocyte development. Whole-cell patch clamp revealed large depolarization (>35 mV) of Kir4.1 cKO astrocytes and oligodendrocytes. Complex cell depolarization appears to be a direct consequence of Kir4.1 removal. In contrast, passive astrocyte depolarization seems to arise from an indirect process that may involve a change in Na+/K+-ATPase function. Kir4.1 cKO passive astrocytes displayed a marked impairment of both K+ and glutamate uptake induced by neuronal stimulation. Surprisingly, membrane and action potential properties of CA1 pyramidal neurons, as well as basal synaptic transmission due to single pulse stimulation appeared unaffected, while spontaneous neuronal activity was reduced in the Kir4.1 cKO. However, increased synaptic stimulation (100 pulse train) revealed greatly elevated (>20%) post-tetanic potentiation and short-term potentiation in Kir4.1 cKO hippocampus. Our findings implicate that through its involvement in astrocyte development and K+ buffering, Kir4.1 participates in the modulation of synaptic strength thereby modulating neuronal spontaneous activity and synaptic plasticity

Implication of Kir4.1 Channel in Excess Potassium Clearance: An In Vivo Study on Anesthetized Glial-Conditional Kir4.1 Knock-Out Mice

The

Expression of A152T human tau causes age-dependent neuronal dysfunction and loss in transgenic mice.

A152T-variant human tau (hTau-A152T) increases risk for tauopathies, including Alzheimer's disease. Comparing mice with regulatable expression of hTau-A152T or wild-type hTau (hTau-WT), we find age-dependent neuronal loss, cognitive impairments, and spontaneous nonconvulsive epileptiform activity primarily in hTau-A152T mice. However, overexpression of either hTau species enhances neuronal responses to electrical stimulation of synaptic inputs and to an epileptogenic chemical. hTau-A152T mice have higher hTau protein/mRNA ratios in brain, suggesting that A152T increases production or decreases clearance of hTau protein. Despite their functional abnormalities, aging hTau-A152T mice show no evidence for accumulation of insoluble tau aggregates, suggesting that their dysfunctions are caused by soluble tau. In human amyloid precursor protein (hAPP) transgenic mice, co-expression of hTau-A152T enhances risk of early death and epileptic activity, suggesting copathogenic interactions between hTau-A152T and amyloid-β peptides or other hAPP metabolites. Thus, the A152T substitution may augment risk for neurodegenerative diseases by increasing hTau protein levels, promoting network hyperexcitability, and synergizing with the adverse effects of other pathogenic factors

Defective Barrier Function in Neosquamous Epithelium

Radiofrequency ablation (RFA) of Barrett’s esophagus (BE) is a common strategy for the prevention of esophageal adenocarcinoma (EAC). After RFA, the ablated esophagus heals on acid suppressive therapy, and is re-populated with a stratified squamous epithelium, referred to as ‘neosquamous epithelium (NSE).’ Because the ability of the NSE to protect the underlying tissue from recurrent insult by reflux is unclear, we assessed the barrier function of NSE by comparing it to that of the native upper squamous epithelium (USE) in subjects having undergone RFA

Conditional Knock-Out of Kir4.1 Leads to Glial Membrane Depolarization, Inhibition of Potassium and Glutamate Uptake, and Enhanced Short-Term Synaptic Potentiation

During neuronal activity, extracellular potassium concentration ([

Role of E-cadherin in the Pathogenesis of Gastroesophageal Reflux Disease

An early event in the pathogenesis of gastroesophageal reflux disease (GERD) is an acid-induced increase in junctional (paracellular) permeability in esophageal epithelium (EE). The molecular events that account for this change are unknown. E-cadherin is a junctional protein important in barrier function in EE. Therefore, defects in barrier function in EE were sought in GERD as well as whether their presence correlated with abnormalities in e-cadherin

Nickel as a potential disruptor of thyroid function: benchmark modelling of human data

IntroductionNickel (Ni) is one of the well-known toxic metals found in the environment. However, its influence on thyroid function is not explored enough. Hence, the aim of this study was to analyse the potential of Ni to disrupt thyroid function by exploring the relationship between blood Ni concentration and serum hormone levels (TSH, T4, T3, fT4 and fT3), as well as the parameters of thyroid homeostasis (SPINA-GT and SPINA-GD) by using correlation analysis and Benchmark (BMD) concept.MethodsNi concentration was measured by ICP-MS method, while CLIA was used for serum hormone determination. SPINA Thyr software was used to calculate SPINA-GT and SPINA-GD parameters. BMD analysis was performed by PROAST software (70.1). The limitations of this study are the small sample size and the uneven distribution of healthy and unhealthy subjects, limited confounding factors, as well as the age of the subjects that could have influenced the obtained results.Results and discussionThe highest median value for blood Ni concentration was observed for the male population and amounted 8,278 µg/L. Accordingly, the statistically significant correlation was observed only in the male population, for Ni-fT4 and Ni-SPINA-GT pairs. The existence of a dose-response relationship was established between Ni and all the measured parameters of thyroid functions in entire population and in both sexes. However, the narrowest BMD intervals were obtained only in men, for Ni - SPINA-GT pair (1.36-60.9 µg/L) and Ni - fT3 pair (0.397-66.8 µg/L), indicating that even 78.68 and 83.25% of men in our study might be in 10% higher risk of Ni-induced SPINA-GT and fT3 alterations, respectively. Due to the relationship established between Ni and the SPINA-GT parameter, it can be concluded that Ni has an influence on the secretory function of the thyroid gland in men. Although the further research is required, these findings suggest possible role of Ni in thyroid function disturbances

With food to health : proceedings of the 10th International scientific and professional conference

Proceedings contains 13 original scientific papers, 10 professional papers and 2 review papers which were presented at "10th International Scientific and Professional Conference WITH FOOD TO HEALTH", organised in following sections: Nutrition, Dietetics and diet therapy, Functional food and food supplemnents, Food safety, Food analysis, Production of safe food and food with added nutritional value