Kv4.1, a Key Ion Channel For Low Frequency Firing of Dentate Granule Cells, Is Crucial for Pattern Separation.

The dentate gyrus (DG) in the hippocampus may play key roles in remembering distinct episodes through pattern separation, which may be subserved by the sparse firing properties of granule cells (GCs) in the DG. Low intrinsic excitability is characteristic of mature GCs, but ion channel mechanisms are not fully understood. Here, we investigated ionic channel mechanisms for firing frequency regulation in hippocampal GCs using male and female mice, and identified Kv4.1 as a key player. Immunofluorescence analysis showed that Kv4.1 was preferentially expressed in the DG, and its expression level determined by Western blot analysis was higher at 8-week than 3-week-old mice, suggesting a developmental regulation of Kv4.1 expression. With respect to firing frequency, GCs are categorized into two distinctive groups: low-frequency (LF) and high-frequency (HF) firing GCs. Input resistance (Rin) of most LF-GCs is lower than 200 MΩ, suggesting that LF-GCs are fully mature GCs. Kv4.1 channel inhibition by intracellular perfusion of Kv4.1 antibody increased firing rates and gain of the input-output relationship selectively in LF-GCs with no significant effect on resting membrane potential and Rin, but had no effect in HF-GCs. Importantly, mature GCs from mice depleted of Kv4.1 transcripts in the DG showed increased firing frequency, and these mice showed an impairment in contextual discrimination task. Our findings suggest that Kv4.1 expression occurring at late stage of GC maturation is essential for low excitability of DG networks and thereby contributes to pattern separation.SIGNIFICANCE STATEMENT The sparse activity of dentate granule cells (GCs), which is essential for pattern separation, is supported by high inhibitory inputs and low intrinsic excitability of GCs. Low excitability of GCs is thought to be attributable to a high K+ conductance at resting membrane potentials, but this study identifies Kv4.1, a depolarization-activated K+ channel, as a key ion channel that regulates firing of GCs without affecting resting membrane potentials. Kv4.1 expression is developmentally regulated and Kv4.1 currents are detected only in mature GCs that show low-frequency firing, but not in less mature high-frequency firing GCs. Furthermore, mice depleted of Kv4.1 transcripts in the dentate gyrus show impaired pattern separation, suggesting that Kv4.1 is crucial for sparse coding and pattern separation.

Development of a personal passive air sampler for estimating exposure to effective chlorine while using chlorine-based disinfectants.

With an increasing use of indoor disinfectants such as chlorine (Cl2 ) and hypochlorous acid, a convenient sampler for estimating exposure to oxidants, such as effective chlorine, is necessary. Here, we developed a personal passive air sampler (PPAS) composed of a redox dye, o-dianisidine, in a polydimethylsiloxane (PDMS) sheet. o-Dianisidine readily reacts with gaseous oxidants generated by bleach usage, and its color changes as the reaction progresses; hence, personal exposure to effective chlorine could be easily detected by the naked eye, while cumulative exposure could be determined by measuring concentrations of o-dianisidine reacting with it. The PPAS was calibrated, and a sampling rate of 0.00253 m3 /h was obtained using a small test chamber. The PPAS was tested with the help of ten volunteers whose personal exposure to Cl2 -equivalent gas was estimated after bathrooms were cleaned using spray and liquid-type household disinfection products, and the accumulated exposure-gas concentrations ranged from 69 to 408 ppbv and 148 to 435 ppbv, respectively. These PPAS-derived exposure concentrations were approximately two orders lower than those estimated using ConsExpo, suggesting a significant overestimation by prevailing screening models, possibly due to the ignorance of transformation reactions.

Retinoic acid modulation of granule cell activity and spatial discrimination in the adult hippocampus.

Retinoic acid (RA), derived from vitamin A (retinol), plays a crucial role in modulating neuroplasticity within the adult brain. Perturbations in RA signaling have been associated with memory impairments, underscoring the necessity to elucidate RA's influence on neuronal activity, particularly within the hippocampus. In this study, we investigated the cell type and sub-regional distribution of RA-responsive granule cells (GCs) in the mouse hippocampus and delineated their properties. We discovered that RA-responsive GCs tend to exhibit a muted response to environmental novelty, typically remaining inactive. Interestingly, chronic dietary depletion of RA leads to an abnormal increase in GC activation evoked by a novel environment, an effect that is replicated by the localized application of an RA receptor beta (RARß) antagonist. Furthermore, our study shows that prolonged RA deficiency impairs spatial discrimination-a cognitive function reliant on the hippocampus-with such impairments being reversible with RA replenishment. In summary, our findings significantly contribute to a better understanding of RA's role in regulating adult hippocampal neuroplasticity and cognitive functions.

Burst firing is required for induction of Hebbian LTP at lateral perforant path to hippocampal granule cell synapses.

High frequency burst firing is critical in summation of back-propagating action potentials (APs) in dendrites, which may greatly depolarize dendritic membrane potential. The physiological significance of burst firings of hippocampal dentate GCs in synaptic plasticity remains unknown. We found that GCs with low input resistance could be categorized into regular-spiking (RS) and burst-spiking (BS) cells based on their initial firing frequency (Finit) upon somatic rheobase current injection, and investigated how two types of GCs differ in long-term potentiation (LTP) induced by high-frequency lateral perforant pathway (LPP) inputs. Induction of Hebbian LTP at LPP synapses required at least three postsynaptic APs at Finit higher than 100 Hz, which was met in BS but not in RS cells. The synaptically evoked burst firing was critically dependent on persistent Na+ current, which was larger in BS than RS cells. The Ca2+ source for Hebbian LTP at LPP synapses was primarily provided by L-type calcium channels. In contrast, Hebbian LTP at medial PP synapses was mediated by T-type calcium channels, and could be induced regardless of cell types or Finit of postsynaptic APs. These results suggest that intrinsic firing properties affect synaptically driven firing patterns, and that bursting behavior differentially affects Hebbian LTP mechanisms depending on the synaptic input pathway.

Estimating the Bioaccumulation Potential of Hydrophobic Ultraviolet Stabilizers Using Experimental Partitioning Properties.

Although hydrophobic ultraviolet (UV) stabilizers are an emerging environmental concern because of their widespread occurrence, persistence, and bioaccumulation potential, experimental values of their partitioning properties required for risk assessment are scarce. In this study, n-octanol-water partition (Kow) and lipid-water partition constants (Klipw), which are key parameters for environmental risk assessment, were experimentally determined for five selected hydrophobic UV stabilizers (UV326, UV327, UV328, UV329, and UV531) based on third-phase partitioning among polydimethylsiloxane (PDMS), water, and n-octanol/lipid. The partition constants between PDMS and water (KPDMSw), obtained using the dynamic permeation method were used to derive Kow and Klipw. The obtained log Kow and log Klipw values were in the ranges of 7.08-7.94 and 7.50-8.34, respectively, indicating that the UV stabilizers exhibited a high bioaccumulation potential in aquatic environments. The experimental Kow and Klipw values obtained in this study provide valuable information for the evaluation of the fate, distribution, bioavailability, and toxicity of the UV stabilizers in aquatic environments.

Highly Flexible Fabrics/Epoxy Composites with Hybrid Carbon Nanofillers for Absorption-Dominated Electromagnetic Interference Shielding.

Epoxy-based nanocomposites can be ideal electromagnetic interference (EMI)-shielding materials owing to their lightness, chemical inertness, and mechanical durability. However, poor conductivity and brittleness of the epoxy resin are challenges for fast-growing portable and flexible EMI-shielding applications, such as smart wristband, medical cloth, aerospace, and military equipment. In this study, we explored hybrid nanofillers of single-walled carbon nanotubes (SWCNT)/reduced graphene oxide (rGO) as conductive inks and polyester fabrics (PFs) as a substrate for flexible EMI-shielding composites. The highest electrical conductivity and fracture toughness of the SWCNT/rGO/PF/epoxy composites were 30.2 S m-1 and 38.5 MPa m1/2, which are ~ 270 and 65% enhancement over those of the composites without SWCNTs, respectively. Excellent mechanical durability was demonstrated by stable electrical conductivity retention during 1000 cycles of bending test. An EMI-shielding effectiveness of ~ 41 dB in the X-band frequency of 8.2-12.4 GHz with a thickness of 0.6 mm was obtained with an EM absorption-dominant behavior over a 0.7 absorption coefficient. These results are attributed to the hierarchical architecture of the macroscale PF skeleton and nanoscale SWCNT/rGO networks, leading to superior EMI-shielding performance. We believe that this approach provides highly flexible and robust EMI-shielding composites for next-generation wearable electronic devices.

Spatial Uncertainty in Modeling Inhalation Exposure to Volatile Organic Compounds in Response to the Application of Consumer Spray Products.

(1) Background: Mathematical exposure modeling of volatile organic compounds (VOCs) in consumer spray products mostly assumes instantaneous mixing in a room. This well-mixed assumption may result in the uncertainty of exposure estimation in terms of spatial resolution. As the inhalation exposure to chemicals from consumer spray products may depend on the spatial heterogeneity, the degree of uncertainty of a well-mixed assumption should be evaluated under specific exposure scenarios. (2) Methods: A room for simulation was divided into eight compartments to simulate inhalation exposure to an ethanol trigger and a propellant product. Real-time measurements of the atmospheric concentration in a room-sized chamber by proton transfer reaction mass spectrometry were compared with mathematical modeling to evaluate the non-homogeneous distribution of chemicals after their application. (3) Results: The well-mixed model overestimated short-term exposure, particularly under the trigger spray scenario. The uncertainty regarding the different chemical proportions in the trigger did not significantly vary in this study. (4) Conclusions: Inhalation exposure to aerosol generating sprays should consider the spatial uncertainty in terms of the estimation of short-term exposure.

Evaluating the fate of hexabromocyclododecanes in the coastal environment: Fugacity analysis using field data.

Abundant use of plastic materials has increased the amount of microplastics (MPs) and related hazardous chemicals in the marine environment. Hexabromocyclododecanes (HBCDs), brominated flame retardants added to expanded polystyrene (EPS), have been detected in biotic and abiotic samples. In this study, the partition constants of HBCDs between plastics and seawater (KPsw) were determined. Fugacities of HBCDs in EPS, seawater, sediment, and mussels were obtained to determine the directions of the diffusive flux. The fugacities in EPS (fEPS) were greater than those in seawater (fsw), sediment (fsed), and mussels (fswmussel-EPS and fmussel-rock) by three orders of magnitude, indicating that EPS plastics are a significant source of HBCDs. The fmussel-rock of α-HBCD in rock mussels was greater than fsw by factors of 1.7, whereas the fmussel-rock of γ-HBCD was smaller than fsw by factors of 16, indicating the bioisomerization from γ-to α-HBCD. The relatively constant concentration ratio of ß-HBCD to the total HBCDs indicated that ß-HBCD is a sufficient tracer for determining the diffusive flux. The fsed values of HBCDs were greater than fsw by factors of 17-28, implying a probable advective vertical flow of HBCDs from the EPS plastics, which requires further investigation.

Impaired pattern separation in Tg2576 mice is associated with hyperexcitable dentate gyrus caused by Kv4.1 downregulation.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that causes memory loss. Most AD researches have focused on neurodegeneration mechanisms. Considering that neurodegenerative changes are not reversible, understanding early functional changes before neurodegeneration is critical to develop new strategies for early detection and treatment of AD. We found that Tg2576 mice exhibited impaired pattern separation at the early preclinical stage. Based on previous studies suggesting a critical role of dentate gyrus (DG) in pattern separation, we investigated functional changes in DG of Tg2576 mice. We found that granule cells in DG (DG-GCs) in Tg2576 mice showed increased action potential firing in response to long depolarizations and reduced 4-AP sensitive K+-currents compared to DG-GCs in wild-type (WT) mice. Among Kv4 family channels, Kv4.1 mRNA expression in DG was significantly lower in Tg2576 mice. We confirmed that Kv4.1 protein expression was reduced in Tg2576, and this reduction was restored by antioxidant treatment. Hyperexcitable DG and impaired pattern separation in Tg2576 mice were also recovered by antioxidant treatment. These results highlight the hyperexcitability of DG-GCs as a pathophysiologic mechanism underlying early cognitive deficits in AD and Kv4.1 as a new target for AD pathogenesis in relation to increased oxidative stress.

Calbindin regulates Kv4.1 trafficking and excitability in dentate granule cells via CaMKII-dependent phosphorylation.

Calbindin, a major Ca2+ buffer in dentate granule cells (GCs), plays a critical role in shaping Ca2+ signals, yet how it regulates neuronal function remains largely unknown. Here, we found that calbindin knockout (CBKO) mice exhibited dentate GC hyperexcitability and impaired pattern separation, which co-occurred with reduced K+ current due to downregulated surface expression of Kv4.1. Relatedly, manipulation of calbindin expression in HT22 cells led to changes in CaMKII activation and the level of surface localization of Kv4.1 through phosphorylation at serine 555, confirming the mechanism underlying neuronal hyperexcitability in CBKO mice. We also discovered that Ca2+ buffering capacity was significantly reduced in the GCs of Tg2576 mice to the level of CBKO GCs, and this reduction was restored to normal levels by antioxidants, suggesting that calbindin is a target of oxidative stress. Our data suggest that the regulation of CaMKII signaling by Ca2+ buffering is crucial for neuronal excitability regulation.

Exposure to permethrin used as a home insecticide: A case study comparing model predictions and excretion of metabolites.

Pyrethroids have been widely used as an active ingredient in home insecticide products since the 1960 s. Although their occurrence in indoor environments has been studied, the contribution of home insecticide application to the aggregate exposure to pyrethroids is not well known. The objective of this study was to estimate the consumer exposure to permethrin, a representative pyrethroid, via the use of home insecticide spray during the summer season using biomonitoring and personal exposure modeling. Exposure to permethrin was assessed by analyzing its urinary metabolites, 3-phenoxybenzoic acid (3-PBA) and cis/trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropan carboxylic acid (cis/trans-DCCA), for a group of consumers (n = 27). The levels of metabolites were also compared with those predicted by a screening exposure model considering personal exposure parameters. The levels of metabolites in 15 participants increased significantly (p < 0.05) with the application of home insecticide products, thereby suggesting that the heavy use of home insecticides during summer could be an important exposure route of permethrin in addition to other sources, such as food consumption. The total amount of excreted 3-PBA and cis/trans-DCCA was lower than the amount estimated by the exposure model for most participants by a factor of 0.9-861.0. These differences could be attributed to the rapid loss of permethrin after application, including sorption to indoor surfaces, reaction with indoor substances, individual biological variations, and ventilation during application. However, the screening exposure model used for the initial safety assessment of biocidal products generally performed well because it did not underestimate the personal exposure to permethrin during the application of home insecticide spray.

Dendritic spikes in hippocampal granule cells are necessary for long-term potentiation at the perforant path synapse.

Long-term potentiation (LTP) of synaptic responses is essential for hippocampal memory function. Perforant-path (PP) synapses on hippocampal granule cells (GCs) contribute to the formation of associative memories, which are considered the cellular correlates of memory engrams. However, the mechanisms of LTP at these synapses are not well understood. Due to sparse firing activity and the voltage attenuation in their dendrites, it remains unclear how associative LTP at distal synapses occurs. Here, we show that NMDA receptor-dependent LTP can be induced at PP-GC synapses without backpropagating action potentials (bAPs) in acute rat brain slices. Dendritic recordings reveal substantial attenuation of bAPs as well as local dendritic Na+ spike generation during PP-GC input. Inhibition of dendritic Na+ spikes impairs LTP induction at PP-GC synapse. These data suggest that dendritic spikes may constitute a key cellular mechanism for memory formation in the dentate gyrus.

Long-term outcome of crossover femoro-femoro-popliteal bypass using side-to-side anastomosis in ilio-femoral occlusive disease.

PURPOSE: During crossover femoro-femoro-popliteal sequential bypass (CFFPB) surgery in ilio-femoral occlusive disease, proximal anastomosis of the femoro-popliteal bypass is usually performed distal to the distal anastomosis of the crossover femoro-femoral bypass. If not, it is done with a piggyback configuration. Another method is a side-to-side anastomosis. Its benefit is that this is the only anastomosis made. And it is less bulky compared with the piggyback configuration. This study was aimed to investigate the long-term outcome of CFFPB using side-to-side anastomosis. METHODS: From Sep 2006 to Aug 2012, 21 patients who underwent CFFPB using side-to-side anastomosis were enrolled. Externally supported polytetrafluoroethylene graft was used as a conduit in all patients. Patient demographic data and procedure details were investigated. Primary graft patency was calculated using the Kaplan-Meier method. RESULTS: The mean age of patients was 79 years (range, 62-81 years) and males were 17 (81%). Fifteen patients (71%) had critical limb ischemia. Inflow arteries comprised of 16 common femoral artery (CFA), 4 superficial femoral artery (SFA), and 1 deep femoral artery (DFA). Side-to-side anastomosis was performed on the CFA in 11, SFA in 2, and DFA in 8 patients. During the mean follow-up period of 21 months (1-60 months), 8 patients died. The 1-, 3-, and 5-year primary patency rates were 76%, 63%, and 63%. CONCLUSION: Long-term patency of CFFPB using side-to-side anastomosis was acceptable. It can be one of the treatment options for patients with ilio-femoral occlusive disease.