Gut microbiome diversity in a febrile seizure mouse model.

Purpose: Febrile seizures at a young age can provoke late-onset temporal lobe epilepsy. Since recent evidence has suggested that the gut microbiome affects central nervous system pathology across the blood-brain barrier, we hypothesized that febrile seizures alter the composition of the gut microbiome to provoke epilepsy. Methods: Third-generation C57BL/6 mice were separated into two groups (n = 5 each), and hot air was applied to only one group to cause febrile seizures. After two weeks of heat challenge, the fecal pellets acquired from each group were analyzed. Results: The gut microbiota of fecal pellets from each group revealed five taxa at the genus level and eight taxa at the species level that were significantly different in proportion between the groups. Conclusion: Although there was no significant difference in the overall diversity of the gut microbiota between the two groups, the identified heterogeneity may imply the pathognomonic causative relevance of febrile seizures and the development of epilepsy.

Therapeutic Target MicroRNA Identification Based on Circular RNA Expression Signature After Intracerebral Hemorrhage.

We investigated circular RNA (circRNA) expression pattern from a rat intracerebral hemorrhage (ICH) model and tested therapeutic strategy. Hemorrhagic stroke was induced by stereotactic collagenase injection. Brain was harvested at 1, 3, and 7 days after ICH induction to study circRNA expression. Significantly altered circRNAs from microarray were examined by quantitative real-time polymerase chain reaction. Predicted target microRNA and nearby messenger RNA levels of significantly altered circRNAs were validated from previously published database. Therapeutic strategy based on potential target microRNA of significantly depressed circRNA was examined using in vitro and in vivo hemorrhagic model. Both significantly elevated/downregulated circRNA increased as time passed after ICH: 9, 159, and 704 circRNAs were significantly elevated, whereas 19, 276, and 656 circRNAs were significantly depressed at 1, 3 and 7 days after ICH induction, respectively, out of 13,298 studied circRNAs. The most elevated circRNAs were rno_circRNA_002714 and rno_circRNA_002715, which are located closely each other in chromosome 10, within exon sequence of glial fibrillary acidic protein. The most significantly downregulated circRNA was rno_circRNA_016465, which has several complementary sequences for miR-466b. The most commonly predicted microRNA response element of significantly depressed circRNAs was miR-466b. The antagonistic sequence against miR-466b significantly decreased neuronal cell death and improved neurological recovery in a hemorrhagic stroke model by upregulating insulin like growth factor receptors 1 and 2. This study illustrated dynamic circRNA expression pattern in a hemorrhagic stroke model, which correlated with microRNA and messenger RNA expression, suggesting the regulatory role of RNA dynamics in ICH.

The effects of heavy rain on the fate of urban and agricultural pollutants in the riverside area around weirs using multi-isotope, microbial data and numerical simulation.

The increase in extreme heavy rain due to climate change is a critical factor in the fate of urban and agricultural pollutants in aquatic system. Nutrients, including NO3- and PO43-, are transported with surface and seepage waters into rivers, lakes and aquifers and can eventually lead to algal blooms. δ15N-NO3-, δ18O-NO3-, and δ11B combined with hydrogeochemical and microbial data for groundwater and surface water samples were interpreted to evaluate the fate of nutrients in a riverside area around weirs in Daegu, South Korea. Most of the ions showed similar concentrations in the groundwater samples before and after heavy rain while concentrations of major ions in surface water samples were diluted after heavy rain. However, Si, PO43-, Zn, Ce, La, Pb, Cu and a number of waterborne pathogens increased in surface water after heavy rain. The interpretation of δ11B, δ15N-NO3-, and δ18O-NO3- values using a Bayesian mixing model revealed that sewage and synthetic fertilizers were the main sources of contaminants in the groundwater and surface water samples. δ18O and SiO2 interpreted using the Bayesian mixing model indicated that the groundwater component in the surface water increased from 4.4 % to 17.9 % during the wet season. This is consistent with numerical simulation results indicating that the direct surface runoff and the groundwater baseflow contributions to the river system had also increased 6.4 times during the wet season. The increase in proteobacteria and decrease of actinobacteria in the surface water samples after heavy rain were also consistent with an increase of surface runoff and an increased groundwater component in the surface water. This study suggests that source apportionment based on chemical and multi-isotope data combined with numerical modeling approaches can be useful for identifying main hydrological and geochemical processes in riverside areas around weirs and can inform suggestions of effective methods for water quality management.

Estimation of nutrient sources and fate in groundwater near a large weir-regulated river using multiple isotopes and microbial signatures.

The excessive input of nutrients into groundwater can accelerate eutrophication in associated surface water systems. This study combined hydrogeochemistry, multi isotope tracers, and microbiological data to estimate nutrient sources and the effects of groundwater-surface water interactions on the spatiotemporal variation of nutrients in groundwater connected to a large weir-regulated river in South Korea. δ11B and δ15N-NO3- values, in combination with a Bayesian mixing model, revealed that manure and sewage contributed 40 % and 25 % respectively to groundwater nitrate, and 42 % and 27 % to nitrate in surface water during the wet season. In the dry season, the source apportionment was similar for groundwater while the sewage contribution increased to 52 % of nitrate in river water. River water displayed a high correlation between NO3- concentration and cyanobacteria (Microcystis and Prochlorococcus) in the wet season. The mixing model using multiple isotopes indicated that manure-derived nutrients delivered with increased contributions of groundwater to the river during the wet season governed the occurrence of cyanobacterial blooms in the river. We postulate that the integrated approach using multi-isotopic and microbiological data is highly effective for evaluating nutrient sources and for delineating hydrological interactions between groundwater and surface water, as well as for investigating surface water quality including eutrophication in riverine and other surface water systems.

Proteins related to ictogenesis and seizure clustering in chronic epilepsy.

Seizure clustering is a common phenomenon in epilepsy. Protein expression profiles during a seizure cluster might reflect the pathomechanism underlying ictogenesis. We performed proteomic analyses to identify proteins with a specific temporal expression pattern in cluster phases and to demonstrate their potential pathomechanistic role. Pilocarpine epilepsy model mice with confirmed cluster pattern of spontaneous recurrent seizures by long-term video-electroencpehalography were sacrificed at the onset, peak, or end of a seizure cluster or in the seizure-free period. Proteomic analysis was performed in the hippocampus and the cortex. Differentially expressed proteins (DEPs) were identified and classified according to their temporal expression pattern. Among the five hippocampal (HC)-DEP classes, HC-class 1 (66 DEPs) represented disrupted cell homeostasis due to clustered seizures, HC-class 2 (63 DEPs) cluster-onset downregulated processes, HC-class 3 (42 DEPs) cluster-onset upregulated processes, and HC-class 4 (103 DEPs) consequences of clustered seizures. Especially, DEPs in HC-class 3 were hippocampus-specific and involved in axonogenesis, synaptic vesicle assembly, and neuronal projection, indicating their pathomechanistic roles in ictogenesis. Key proteins in HC-class 3 were highly interconnected and abundantly involved in those biological processes. This study described the seizure cluster-associated spatiotemporal regulation of protein expression. HC-class 3 provides insights regarding ictogenesis-related processes.

Differentiation of natural and anthropogenic contaminant sources using isotopic and microbial signatures in a heavily cultivated coastal area.

Hydrogeochemical and multiple isotope data for groundwater samples were obtained and interpreted to discriminate anthropogenic and natural contaminant sources in a coastal aquifer underlying a heavily cultivated watershed in Hwaseong, South Korea. The local aquifers are vulnerable to contamination, due to high anthropogenic N inputs and the location close to the ocean facilitating seawater intrusion. Thus, to effectively control the groundwater quality in the study area, it is necessary to differentiate between anthropogenic and natural contaminant sources. The concentrations of NO3-N in the groundwater ranged between 0.14 and 45.6 mg/L in August 2015 and 0.2-39.6 mg/L in March 2016. High concentrations of Cl- (388-1107 mg/L) and a high electrical conductivity (1027-2715 µS/cm) were observed in the study area, suggesting that the groundwater was affected by seawater intrusion. Furthermore, δ15N-NO3-, δ34S-SO42- values and 87Sr/86Sr of groundwater were determined to reveal the origins of the natural and anthropogenic contaminants and the groundwater mean residence times (MRT) and 87Sr/86Sr ratios were used to assess the hydrogeochemical processes along the flow path in the study area. Young groundwater was affected by an anthropogenic contamination source with contributions of 26-46% adding nitrate to the aquifer, whereas old groundwater was impacted by mixing with seawater with contributions of 10-20% with low concentrations of NO3-N, but elevated concentrations of chloride and sulfate. Recently recharged uncontaminated groundwater showed oxic conditions with a diverse microbial community structure, whereas young groundwater contaminated by anthropogenic sources showed a less diverse microbial community structure. The results of this study suggest that multiple isotopes combined with groundwater MRT and microbial data can be applied to distinguish natural and anthropogenic contaminant sources in a groundwater system.

CaV α2δ Autoimmune Encephalitis: A Novel Antibody and its Characteristics.

OBJECTIVE: Discovery of a novel antibody would enable diagnosis and early treatment of autoimmune encephalitis. The aim was to discover a novel antibody targeting a synaptic receptor and characterize the pathogenic mechanism. METHOD: We screened for unknown antibodies in serum and cerebrospinal fluid samples from autoimmune encephalitis patients. Samples with reactivity to rat brain sections and no reactivity to conventional antibody tests underwent further processing for antibody discovery, using immunoprecipitation to primary neuronal cells, mass-spectrometry analysis, an antigen-binding assay on an antigen-overexpressing cell line, and an electrophysiological assay with cultured hippocampal neurons. RESULTS: Two patients had a novel antibody against CaV α2δ (voltage-gated calcium channel alpha-2/delta subunit). The patient samples stained neuropils of the hippocampus, basal ganglia, and cortex in rat brain sections and bound to a CaV α2δ-overexpressing cell line. Knockdown of CaV α2δ expression in cultured neurons turned off the immunoreactivity of the antibody from the patients to the neurons. The patients were associated with preceding meningitis or neuroendocrine carcinoma and responded to immunotherapy. In cultured neurons, the antibody reduced neurotransmitter release from presynaptic nerve terminals by interfering with tight coupling of calcium channels and exocytosis. INTERPRETATION: Here, we discovered a novel autoimmune encephalitis associated with anti-CaV α2δ antibody. Further analysis of the antibody in autoimmune encephalitis might promote early diagnosis and treatment. ANN NEUROL 2021;89:740-752.

Altered long noncoding RNA profile after intracerebral hemorrhage.

OBJECTIVE: We investigated the expression pattern of long noncoding RNAs (lncRNA) and messenger RNAs (mRNA) from two different intracerebral hemorrhage (ICH) rat models, and performed gene ontology and gene/protein interaction analyses. METHODS: We harvested hemorrhagic brain 1, 3, and 7 days after ICH induction by stereotactic collagenase injection. We performed microarray analyses with Agilent array platform to compare the expression of lncRNA and mRNAs from hemorrhagic and normal brains. The RNA expression patterns were also examined from the autologous blood injection ICH model at days 1 and 3, and significantly altered lncRNAs from two ICH models were validated by quantitative reverse transcriptase-polymerase chain reaction. Gene ontology analysis and pathway analysis were performed with differentially expressed mRNAs after ICH. Gene and protein interaction analysis was performed to elucidate the functional role of upregulated lncRNA in neuronal damage. RESULTS: Among the 13,661 lncRNAs studied, 83, 289, and 401 lncRNAs were significantly elevated after 1, 3, and 7 days after collagenase-induced ICH, respectively. NR_027324, or H19, was the most upregulated lncRNA after 1 day from the two ICH models and its elevation persisted until the 7th day. Gene ontology analysis revealed that immune-related biological processes such as immune response, immune system process, and defense response were upregulated from both ICH models. Gene and protein interaction study demonstrated that NR_027324 was closely related to the type I interferon signaling pathway. INTERPRETATION: This study illustrates the dynamic expression pattern of the lncRNA profile following ICH, and that H19 is the most consistently upregulated lncRNA after ICH.

Possible epigenetic regulatory effect of dysregulated circular RNAs in Alzheimer's disease model.

As circular RNAs (circRNAs) regulates the effect of micro RNAs (miRNAs), circRNA-miRNA-mRNA network might be implicated in various disease pathogenesis. Therefore, we evaluated the dysregulated circRNAs in the Tg2576 mouse Alzheimer's disease (AD) model, their possible regulatory effects on downstream target mRNAs, and their pathomechanistic role during the disease progression. The microarray-based circRNA expression analysis at seven- and twelve-months of ages (7 M and 12 M) returned 101 dysregulated circRNAs at 7 M (55 up-regulated and 46 down-regulated) and twelve dysregulated circRNAs at 12 M (five up-regulated and seven down-regulated). For each dysregulated circRNA, potential target miRNAs and their downstream target mRNAs were searched. Dysregulation of circRNAs was associated with increased frequency of relevant dysregulation of their downstream target mRNAs. Those differentially expressed circRNA-miRNA-mRNA regulatory network included 2,275 networks (876 for up-regulated circRNAs and 1,399 for down-regulated circRNAs) at 7 M and 38 networks (25 for up-regulated circRNAs and 13 for down-regulated circRNAs) at 12 M. Gene ontology (GO) and pathway analyses demonstrated that the dysregulated mRNAs in those networks represent the AD pathomechanism at each disease stage. We concluded that the dysregulated circRNAs might involve in the AD pathogenesis by modulating disease relevant mRNAs via circRNA-miRNA-mRNA regulatory networks.

Possible epigenetic regulatory effect of dysregulated circular RNAs in epilepsy.

Circular RNAs (circRNAs) involve in the epigenetic regulation and its major mechanism is the sequestration of the target micro RNAs (miRNAs). We hypothesized that circRNAs might be related with the pathophysiology of chronic epilepsy and evaluated the altered circRNA expressions and their possible regulatory effects on their target miRNAs and mRNAs in a mouse epilepsy model. The circRNA expression profile in the hippocampus of the pilocarpine mice was analyzed and compared with control. The correlation between the expression of miRNA binding sites (miRNA response elements, MRE) in the dysregulated circRNAs and the expression of their target miRNAs was evaluated. As miRNAs also inhibit their target mRNAs, circRNA-miRNA-mRNA regulatory network, comprised of dysregulated RNAs that targets one another were searched. For the identified networks, bioinformatics analyses were performed. As the result, Forty-three circRNAs were dysregulated in the hippocampus (up-regulated, 26; down-regulated, 17). The change in the expression of MRE in those circRNAs negatively correlated with the change in the relevant target miRNA expression (r = -0.461, P<0.001), supporting that circRNAs inhibit their target miRNA. 333 dysregulated circRNA-miRNA-mRNA networks were identified. Gene ontology and pathway analyses demonstrated that the up-regulated mRNAs in those networks were closely related to the major processes in epilepsy. Among them, STRING analysis identified 37 key mRNAs with abundant (≥4) interactions with other dysregulated target mRNAs. The dysregulation of the circRNAs which had multiple interactions with key mRNAs were validated by PCR. We concluded that dysregulated circRNAs might have a pathophysiologic role in chronic epilepsy by regulating multiple disease relevant mRNAs via circRNA-miRNA-mRNA interactions.

Maternal immune activation alters brain microRNA expression in mouse offspring.

OBJECTIVE: Maternal immune activation (MIA) is associated with an increased risk of autism spectrum disorder (ASD) in offspring. Herein, we investigate the altered expression of microRNAs (miRNA), and that of their target genes, in the brains of MIA mouse offspring. METHODS: To generate MIA model mice, pregnant mice were injected with polyriboinosinic:polyribocytidylic acid on embryonic day 12.5. We performed miRNA microarray and mRNA sequencing in order to determine the differential expression of miRNA and mRNA between MIA mice and controls, at 3 weeks of age. We further identified predicted target genes of dysregulated miRNAs, and miRNA-target interactions, based on the inverse correlation of their expression levels. RESULTS: Mice prenatally subjected to MIA exhibited behavioral abnormalities typical of ASD, such as a lack of preference for social novelty and reduced prepulse inhibition. We found 29 differentially expressed miRNAs (8 upregulated and 21 downregulated) and 758 differentially expressed mRNAs (542 upregulated and 216 downregulated) in MIA offspring compared to controls. Based on expression levels of the predicted target genes, 18 downregulated miRNAs (340 target genes) and three upregulated miRNAs (60 target genes) were found to be significantly enriched among the differentially expressed genes. miRNA and target gene interactions were most significant between mmu-miR-466i-3p and Hfm1 (ATP-dependent DNA helicase homolog), and between mmu-miR-877-3p and Aqp6 (aquaporin 6). INTERPRETATION: Our results provide novel information regarding miRNA expression changes and their putative targets in the early postnatal period of brain development. Further studies will be needed to evaluate potential pathogenic roles of the dysregulated miRNAs.

Dysregulated long non-coding RNAs in the temporal lobe epilepsy mouse model.

PURPOSE: To perform comprehensive profiling of long non-coding RNAs (LncRNAs) in temporal lobe epilepsy. METHODS: We performed extensive profiling of LncRNAs and mRNAs in the mouse pilocarpine model in specific brain regions, the hippocampus and cortex, and compared the results to those of the control mouse. Differentially expressed LncRNAs and mRNAs were identified with a microarray analysis (Arraystar Mouse LncRNA Expression Microarray V3.0). Then, gene ontology (GO) and pathway analysis were performed to investigate the potential roles of the differentially expressed mRNAs in the pilocarpine model. Protein-protein interactions transcribed by dysregulated mRNAs with/without co-dysregulated LncRNAs were analyzed using STRING v10 (http://string-db.org/). RESULTS: A total of 22 and 83 LncRNAs were up- and down-regulated (≥2.0-fold, all P < .05), respectively, in the hippocampus of the epilepsy model, while 46 and 659 LncRNAs were up- and down-regulated, respectively, in the cortex of the epilepsy model. GO and pathway analysis revealed that the dysregulated mRNAs were closely associated with a process already known to be involved in epileptogenesis: acute inflammation, calcium ion regulation, extracellular matrix remodeling, and neuronal differentiation. Among the LncRNAs, we identified 10 LncRNAs commonly dysregulated with corresponding mRNAs in the cortex. The STRING analysis showed that the dysregulated mRNAs were interconnected around two centers: the mTOR pathway-related genes and REST pathway-related genes. CONCLUSION: LncRNAs were dysregulated in the pilocarpine mouse model according to the brain regions of the hippocampus and cortex. The dysregulated LncRNAs with co-dysregulated mRNAs might be possible therapeutic targets for the epigenetic regulation of chronic epilepsy.

Neurovascular Cell Sheet Transplantation in a Canine Model of Intracranial Hemorrhage.

Cell-based therapy for intracerebral hemorrhage (ICH) has a great therapeutic potential. However, methods to effectively induce direct regeneration of the damaged neural tissue after cell transplantation have not been established, which, if done, would improve the efficacy of cell-based therapy. In this study, we aimed to develop a cell sheet with neurovasculogenic potential and evaluate its usefulness in a canine ICH model. We designed a composite cell sheet made of neural progenitors derived from human olfactory neuroepithelium and vascular progenitors from human adipose tissue-derived stromal cells. We also generated a physiologic canine ICH model by manually injecting and then infusing autologous blood under arterial pressure. We transplanted the sheet cells (cell sheet group) or saline (control group) at the cortex over the hematoma at subacute stages (2 weeks from ICH induction). At 4 weeks from the cell transplantation, cell survival, migration, and differentiation were evaluated. Hemispheric atrophy and neurobehavioral recovery were also compared between the groups. As a result, the cell sheet was rich in extracellular matrices and expressed neurotrophic factors as well as the markers for neuronal development. After transplantation, the cells successfully survived for 4 weeks, and a large portion of those migrated to the perihematomal site and differentiated into neurons and pericytes (20% and 30% of migrated stem cells, respectively). Transplantation of cell sheets alleviated hemorrhage-related hemispheric atrophy (p = 0.042) and showed tendency for improving functional recovery (p = 0.062). Therefore, we concluded that the cell sheet transplantation technique might induce direct regeneration of neural tissue and might improve outcomes of intracerebral hemorrhage.

Inhibition of miR-203 Reduces Spontaneous Recurrent Seizures in Mice.

Inhibitory synaptic receptors are dysfunctional in epileptic brains, and agents that selectively target these receptors may be effective for the treatment of epilepsy. MicroRNAs interfere with the translation of target genes, including various synaptic proteins. Here, we show that miR-203 regulates glycine receptor-ß (Glrb) in epilepsy models. miR-203 is upregulated in the hippocampus of epileptic mice and human epileptic brains and is predicted to target inhibitory synaptic receptors, including Glrb. In vitro transfection, target gene luciferase assays, and analysis of human samples confirmed the direct inhibition of GLRB by miR-203, and AM203, an antagomir targeting miR-203, reversed the effect of miR-203. When intranasal AM203 was administered, AM203 reached the brain and restored hippocampal GLRB levels in epileptic mice. Finally, intranasal AM203 reduced the epileptic seizure frequency of mice. Overall, this study suggests that GLRB expression in the epileptic brain is controlled by miR-203, and intranasal delivery of AM203 showed therapeutic effects in chronic epilepsy mice.

Experimental Induction of Cerebral Aneurysms by Developmental Low Copper Diet.

Optimal models are needed to understand the pathophysiology of human cerebral aneurysms (CA). We investigated the development of experimental CA by decreasing the activity of lysyl oxidases by dietary copper deficiency from the time of gestation and then augmenting vascular stress by angiotensin II infusion in adulthood. Rats were fed copper-free, low-copper, or normal diets at different time periods from gestation to adulthood. The incidences of CAs were evaluated and autopsies performed to determine the coexistence of cardiovascular diseases. A copper-free diet from gestation was associated with high mortality rates (79.1%) resulting from rupture of ascending aorta aneurysms; a low-copper diet led to acceptable mortality rates (13.6%) and produced CAs and subarachnoid hemorrhage in 46.4% and 3.6% of animals, respectively. Higher proportions of CAs (up to 33.3%) in the rats primed for copper deficiency from gestation ruptured following angiotensin II infusion from adulthood. Gene expression array analyses of the CAs indicated that genes involving extracellular matrix and vascular remodeling were altered in this model. This model enables future research to understand the entire pathogenetic basis of CA development and rupture in association with systemic vasculopathies.

Vitamin D deficiency and its relationship with endothelial dysfunction in patients with early Parkinson's disease.

Increasing evidence has shown that individuals with Parkinson's disease (PD) have lower levels of 25-hydroxyvitamin D (25[OH]D) than healthy controls. Low vitamin D has been associated with endothelial dysfunction which may play a role in the pathogenesis and progression of PD. Flow-mediated dilation (FMD) is widely used as a clinical marker of overall endothelial function. We evaluated the relationship between serum 25(OH)D levels and FMD in PD. We enrolled 81 patients with early PD and 52 healthy controls, and we evaluate endothelial function based on vitamin D status and identify the association between FMD and vitamin D status in patients with early PD. The mean serum 25(OH)D levels were significantly lower in the PD patients than in the controls (21.8 ± 9.5 vs. 25.2 ± 9.3 ng/mL, p < 0.05). FMD was significantly lower in the PD patients (7.1 ± 1.8 %) than in the controls (8.1 ± 2.1 %, p < 0.05). The serum 25(OH)D was significantly associated with FMD independently of age, cardiovascular disease risk factors, body mass index, motor Unified PD Rating Scale status and homocysteine levels (adjusted R (2) = 0.331, ß = 0.494, p < 0.001). These findings provide evidence of a possible association between endothelial dysfunction as assessed by FMD and low vitamin D status in patients with early PD.

Enhanced Performance in Bulk Heterojunction Polymer Solar Cell Using Water Soluble Conjugated Polymer.

We have synthesized water-soluble polymer, poly[(9,9-bis((6'-(N,N,N-trimethylammonium)hexyl)-2,7-fluorene))-alt-bisphenylfumaronitrile]dibromide (AHF-alt-PFN), the polymer typically obtained by the Suzuki type of polymerization reaction and shows good solubility in methanol. Bulk heterojunction polymer solar cells (BHJ-PSCs) fabricated by using water soluble conjugated polymer and positive (Cs+) and negative (F-, CO2-(3)) charge ions doping as an interfacial layer for poly(3-hexylthiophene):phenyl-C61 butyric acid methyl ester (P3HT:PCBM). We have achieved an enhancement of the short circuit density and power conversion efficiency in solar cell by introducing poly(AHF-alt-PFN) layer between the active layer and the cathode metal. The device with poly(AHF-alt-PRN) layer containing F-, CO2-(3) showed a short circuit current density more 1.3, 2.3 times higher than those of the device without poly(AHF-alt-PFN) + ion layer. We explain the better performance in solar cell with poly(AHF-alt-PFN) + ion layer was due not only to the increase of electron mobility in poly(AHF-alt-PFN) layer but also to the decrease of the electron barrier near cathode by the addition of the negative ions.

Dysregulation of long non-coding RNAs in mouse models of localization-related epilepsy.

Genome-wide profiling has revealed that eukaryotic genomes are transcribed into numerous non-coding RNAs. In particular, long non-coding RNAs (lncRNAs) have been implicated in various human diseases due to their biochemical and functional diversity. Epileptic disorders have been characterized by dysregulation of epigenetic regulatory mechanisms, and recent studies have identified several lncRNAs involved in neural development and network function. However, comprehensive profiling of lncRNAs implicated in chronic epilepsy has been lacking. In this study, microarray analysis was performed to obtain the expression profile of lncRNAs dysregulated in pilocarpine and kainate models, two models of temporal lobe epilepsy commonly used for studying epileptic mechanisms. Total of 4622 lncRNAs were analyzed: 384 lncRNAs were significantly dysregulated in pilocarpine model, and 279 lncRNAs were significantly dysregulated in kainate model compared with control mice (≥3.0-fold, p < 0.05). Among these, 54 and 14 lncRNAs, respectively, had adjacent protein-coding genes whose expressions were also significantly dysregulated (≥2.0-fold, p < 0.05). Majority of these pairs of lncRNAs and adjacent genes shared the same direction of dysregulation. For the selected adjacent gene-lncRNA pairs, significant Gene Ontology terms were embryonic appendage morphogenesis and neuron differentiation. This was the first study to comprehensively identify dysregulated lncRNAs in two different models of chronic epilepsy and will likely provide a novel insight into developing lncRNA therapeutics.

Distinct Expression of Long Non-Coding RNAs in an Alzheimer's Disease Model.

With the recent advancement in transcriptome-wide profiling approach, numerous non-coding transcripts previously unknown have been identified. Among the non-coding transcripts, long non-coding RNAs (lncRNAs) have received increasing attention for their capacity to modulate transcriptional regulation. Although alterations in the expressions of non-coding RNAs have been studied in Alzheimer's disease (AD), most research focused on the involvement of microRNAs, and comprehensive expression profiling of lncRNAs in AD has been lacking. In this study, microarray analysis was performed to procure the expression profile of lncRNAs dysregulated in a triple transgenic model of AD (3xTg-AD). A total of 4,622 lncRNAs were analyzed: 205 lncRNAs were significantly dysregulated in 3xTg-AD compared with control mice, and 230 lncRNAs were significantly dysregulated within 3xTg-AD in an age-dependent manner (≥2.0-fold, p < 0.05). Among these, 27 and 15 lncRNAs, respectively, had adjacent protein-coding genes whose expressions were also significantly dysregulated. A majority of these lncRNAs and their adjacent genes shared the same direction of dysregulation. For these pairs of lncRNAs and adjacent genes, significant Gene Ontology terms were DNA-dependent regulation of transcription, transcription regulator activity, and embryonic organ morphogenesis. One of the most highly upregulated lncRNAs had a 395 bp core sequence that overlapped with multiple chromosomal regions. This is the first study that comprehensively identified dysregulated lncRNAs in 3xTg-AD mice and will likely facilitate the development of therapeutics targeting lncRNAs in AD.