Angelman syndrome (AS) is a neurodevelopmental disorder caused by loss of the maternally inherited allele of UBE3A. AS model mice, which carry a maternal Ube3a null mutation (Ube3am−/p+), ...recapitulate major features of AS in humans, including enhanced seizure susceptibility. Excitatory neurotransmission onto neocortical pyramidal neurons is diminished in Ube3am−/p+ mice, seemingly at odds with enhanced seizure susceptibility. We show here that inhibitory drive onto neocortical pyramidal neurons is more severely decreased in Ube3am−/p+ mice. This inhibitory deficit follows the loss of excitatory inputs and appears to arise from defective presynaptic vesicle cycling in multiple interneuron populations. In contrast, excitatory and inhibitory synaptic inputs onto inhibitory interneurons are largely normal. Our results indicate that there are neuron type-specific synaptic deficits in Ube3am−/p+ mice despite the presence of Ube3a in all neurons. These deficits result in excitatory/inhibitory imbalance at cellular and circuit levels and may contribute to seizure susceptibility in AS.
► Inhibitory neurotransmission is reduced in adult Ube3am−/p+ mice ► Inhibition is decreased onto excitatory, but not FS-inhibitory interneurons ► Decreased inhibition arises from multiple inhibitory interneuron classes ► Synaptic vesicle cycling defect may impair inhibitory neurotransmission
Wallace et al. describe a novel defect in vesicular cycling at inhibitory axon terminals in a mouse model of Angelman syndrome. These deficits result in an excitatory/inhibitory imbalance that may contribute to cognitive deficits and seizure susceptibility in AS.
Like nitric oxide and carbon monoxide, hydrogen sulfide has historically been recognized as an industrial pollutant, but in recent years, it has been shown to be an important mediator of many ...physiological processes. Hydrogen sulfide contributes to the maintenance of gastrointestinal mucosal defense and repair. It also exerts many antiinflammatory effects, including inhibition of leukocyte adherence to the vascular endothelium and leukocyte migration to sites of inflammation. Conversely, inhibition of endogenous hydrogen sulfide synthesis leads to a loss of mucosal integrity and to an increase in mucosal inflammation. Hydrogen sulfide therefore appears to have overlapping actions with nitric oxide and prostaglandins in terms of modulating mucosal defense and resolution of inflammation. Recent evidence suggests that these properties of hydrogen sulfide can be exploited in the design of novel therapies for ulcerative and inflammatory diseases of the gastrointestinal tract.
The latest report by the Intergovernmental Panel on Climate Change (IPCC) predicts a 1.4-5.8 °C average increase in the global surface temperature over the period 1990 to 2100 (ref. 1). These ...estimates of future warming are greater than earlier projections, which is partly due to incorporation of a positive feedback. This feedback results from further release of greenhouse gases from terrestrial ecosystems in response to climatic warming. The feedback mechanism is usually based on the assumption that observed sensitivity of soil respiration to temperature under current climate conditions would hold in a warmer climate. However, this assumption has not been carefully examined. We have therefore conducted an experiment in a tall grass prairie ecosystem in the US Great Plains to study the response of soil respiration (the sum of root and heterotrophic respiration) to artificial warming of about 2 °C. Our observations indicate that the temperature sensitivity of soil respiration decreases-or acclimatizes-under warming and that the acclimatization is greater at high temperatures. This acclimatization of soil respiration to warming may therefore weaken the positive feedback between the terrestrial carbon cycle and climate.
Almost half of all children with autism spectrum disorder have average cognitive abilities, yet outcome remains poor. Because outcome in HFASD is more related to adaptive behavior skills than ...cognitive level it is important to identify predictors of adaptive behavior. This study examines cognitive and demographic factors related to adaptive behavior, with specific attention to the role of executive function (EF) in youth with HFASD aged 4–23. There was a negative relationship between age and adaptive behavior and the discrepancy between IQ and adaptive behavior increased with age. EF problems contributed to lower adaptive behavior scores across domains. As such, it is important to target adaptive skills, and the EF problems that may contribute to them, in youth with HFASD.
We present new measurements of the temperature of the intergalactic medium (IGM) derived from the Lyα forest over 2.0 ≤z≤ 4.8. The small-scale structure in the forest of 61 high-resolution ...quasi-stellar object spectra is quantified using a new statistic, the curvature, and the conversion to temperature calibrated using a suite of hydrodynamic simulations. At each redshift, we focus on obtaining the temperature at an optimal overdensity probed by the Lyα forest,
, where the temperature is nearly a one-to-one function of the curvature regardless of the slope of the temperature-density relation. The median 2σ statistical uncertainty in these measurements is 8 per cent, though there may be comparable systematic errors due to the unknown amount of Jeans smoothing in the IGM. We use our
results to infer the temperature at the mean density, T
0. Even for a maximally steep temperature-density relation, T
0 must increase from ∼8000 K at z≃ 4.4 to ≳12 000 K at z≃ 2.8. This increase is not consistent with the monotonic decline in T
0 expected in the absence of He ii reionization. We therefore interpret the observed rise in temperature as evidence of He ii reionization beginning at z≳ 4.4. The evolution of T
0 is consistent with an end to He ii reionization at z∼ 3, as suggested by opacity measurements of the He ii Lyα forest, although the redshift at which T
0 peaks will depend somewhat on the evolution of the temperature-density relation. These new temperature measurements suggest that the heat input due to the reionization of He ii dominates the thermal balance of the IGM over an extended period with Δz≳ 1.
Behavioral studies of facial emotion recognition (FER) in autism spectrum disorders (ASD) have yielded mixed results. Here we address demographic and experiment-related factors that may account for ...these inconsistent findings. We also discuss the possibility that compensatory mechanisms might enable some individuals with ASD to perform well on certain types of FER tasks in spite of atypical processing of the stimuli, and difficulties with real-life emotion recognition. Evidence for such mechanisms comes in part from eye-tracking, electrophysiological, and brain imaging studies, which often show abnormal eye gaze patterns, delayed event-related-potential components in response to face stimuli, and anomalous activity in emotion-processing circuitry in ASD, in spite of intact behavioral performance during FER tasks. We suggest that future studies of FER in ASD: 1) incorporate longitudinal (or cross-sectional) designs to examine the developmental trajectory of (or age-related changes in) FER in ASD and 2) employ behavioral and brain imaging paradigms that can identify and characterize compensatory mechanisms or atypical processing styles in these individuals.
Loss of maternal UBE3A causes Angelman syndrome (AS), a neurodevelopmental disorder associated with severe epilepsy. We previously implicated GABAergic deficits onto layer (L) 2/3 pyramidal neurons ...in the pathogenesis of neocortical hyperexcitability, and perhaps epilepsy, in AS model mice. Here we investigate consequences of selective Ube3a loss from either GABAergic or glutamatergic neurons, focusing on the development of hyperexcitability within L2/3 neocortex and in broader circuit and behavioral contexts. We find that GABAergic Ube3a loss causes AS-like increases in neocortical EEG delta power, enhances seizure susceptibility, and leads to presynaptic accumulation of clathrin-coated vesicles (CCVs)—all without decreasing GABAergic inhibition onto L2/3 pyramidal neurons. Conversely, glutamatergic Ube3a loss fails to yield EEG abnormalities, seizures, or associated CCV phenotypes, despite impairing tonic inhibition onto L2/3 pyramidal neurons. These results substantiate GABAergic Ube3a loss as the principal cause of circuit hyperexcitability in AS mice, lending insight into ictogenic mechanisms in AS.
•Glutamatergic Ube3a loss decreases tonic inhibition onto L2/3 pyramidal neurons•GABAergic Ube3a loss does not compromise inhibition onto L2/3 pyramidal neurons•GABAergic, not glutamatergic, Ube3a loss causes EEG abnormalities and seizures•L2/3 GABAergic defects in AS mice neither cause, nor are caused by, seizures
Judson and colleagues use neuron-type-specific manipulations of maternal Ube3a expression to demonstrate that GABAergic Ube3a loss is sufficient to yield Angelman syndrome-like EEG abnormalities, enhancements in seizure susceptibility, and atypical clathrin-coated vesicle accumulations within presynaptic terminals.
The American Glaucoma Society is surveying its membership to determine the 100 papers that have had the greatest impact on the clinical management of glaucoma patients. When Dr. William Argus ...suggested to me that a paper by Eddy and Billings, a paper that questioned the value of treating glaucoma, should be included, I was horrified. I was a glaucoma fellow in 1987, the year that the Eddy and Billings' work came to light. At that time David Eddy's name evoked the warm, fuzzy feelings usually reserved for dictators and tyrants. It was certainly the most talked-about paper during my fellowship year and the first few years of my career as a glaucoma subspecialist. The paper by Eddy and Billings was discussed with anger and contempt. Their work was the subject of editorial comment that, while acknowledging the gaps in evidence, was concerned that this information would lead to the loss of funding for glaucoma treatment.1 I was embarrassed that I had never actually read the Eddy and Billings paper until I learned from Dr. Argus that the paper was never actually published. Nobody had read it. Well, almost nobody; the reviewers for the Journal of the American Medical Association had read it and apparently circulated it to influential ophthalmologists.2 Word of it spread like wildfire.
We report identification of a novel genetic locus (GLC1P) for normal tension glaucoma (NTG) on chromosome 12q14 using linkage studies of an African-American pedigree (maximum non-parametric linkage ...score = 19.7, max LOD score = 2.7). Subsequent comparative genomic hybridization and quantitative polymerase chain reaction (PCR) experiments identified a 780 kbp duplication within the GLC1P locus that is co-inherited with NTG in the pedigree. Real-time PCR studies showed that the genes within this duplication TBK1 (TANK-binding kinase 1), XPOT, RASSF3 and GNS are all expressed in the human retina. Cohorts of 478 glaucoma patients (including 152 NTG patients), 100 normal control subjects and 400 age-related macular degeneration patients were subsequently tested for copy number variation in GLC1P. Overlapping duplications were detected in 2 (1.3%) of the 152 NTG subjects, one of which had a strong family history of glaucoma. These duplications defined a 300 kbp critical region of GLC1P that spans two genes (TBK1 and XPOT). Microarray expression experiments and northern blot analysis using RNA obtained from human skin fibroblast cells showed that duplication of chromosome 12q14 results in increased TBK1 and GNS transcription. Finally, immunohistochemistry studies showed that TBK1 is expressed in the ganglion cells, nerve fiber layer and microvasculature of the human retina. Together, these data link the duplication of genes on chromosome 12q14 with familial NTG and suggest that an extra copy of the encompassed TBK1 gene is likely responsible for these cases of glaucoma. However, animal studies will be necessary to rule out a role for the other duplicated or neighboring genes.
We develop a kinematic model for the transition from subduction beneath the North Island, New Zealand, to strike‐slip in the South Island, constrained by GPS velocities and active fault slip data. To ...interpret these data, we use an approach that inverts the kinematic data for poles of rotation of tectonic blocks and the degree of interseismic coupling on faults in the region. Convergence related to the Hikurangi subduction margin becomes very low offshore of the northern South Island, indicating that in this region the majority of the relative plate motion has been transferred onto faults within the upper plate, as suggested by previous studies. This result has implications for understanding the likely extent of subduction interface earthquake rupture in central New Zealand. Easterly trending strike slip faults (such as the Boo Boo fault) are the key features that facilitate the transfer of strike‐slip motion from the northern South Island faults further north into the southern North Island and onto the Hikurangi subduction thrust. Our results also indicate that the transition from rapid forearc rotation adjacent to the Hikurangi subduction margin to a strike‐slip dominated plate boundary (with negligible vertical‐axis rotation) in the South Island occurs via a crustal‐scale hinge or kink in the upper plate, compatible with paleomagnetic and structural geological data. Despite the ongoing tectonic evolution of the central New Zealand region, our study highlights a remarkable consistency between data sets spanning decades (GPS), thousands of years (active faulting data), and millions of years (paleomagnetic data and bedrock structure).
Key Points
Active fault and GPS data used to constrain strike‐slip to subduction in NZ
Excellent agreement between short‐term (GPS) and longer‐term (active fault) data
New model for subduction interface coupling at Hikurangi margin
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