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Abstract Background Prader–Willi syndrome (PWS) is a neurodevelopmental disorder characterized by multiple respiratory, cognitive, endocrine, and behavioral symptoms, such as central apnea, intellectual disabilities, exaggerated stress responses, and temper tantrums. The locus coeruleus noradrenergic system (LC-NE) modulates a diverse range of behaviors, including arousal, learning, pain modulation, and stress-induced negative affective states, which are possibly correlated with the pathogenesis of PWS phenotypes. Therefore, we evaluated the LC-NE neuronal activity of necdin-deficient mice, an animal model of PWS. Methods Heterozygous necdin-deficient mice (B6.Cg-Ndntm1ky) were bred from wild-type (WT) females to generate WT (+m/+p) and heterozygotes (+m/−p) animals, which were examined of LC-NE neuronal activity, developmental reflexes, and plethysmography. Results On slice electrophysiology, LC-NE neurons of Ndn tm1ky mice with necdin deficiency showed significantly decreased spontaneous activities and impaired excitability, which was mediated by enhanced A-type voltage-dependent potassium currents. Ndn tm1ky mice also exhibited the neonatal phenotypes of PWS, such as hypotonia and blunt respiratory responses to hypercapnia. Conclusions LC-NE neuronal firing activity decreased in necdin-deficient mice, suggesting that LC, the primary source of norepinephrine in the central nervous system, is possibly involved in PWS pathogenesis.

Epilepsy is a common neurological disorder, which has been linked to mutations or deletions of RNA binding protein, fox-1 homolog ( Caenorhabditis elegans ) 3 ( RBFOX3 )/ NeuN , a neuronal splicing regulator. However, the mechanism of seizure mediation by RBFOX3 remains unknown. Here, we show that mice with deletion of Rbfox3 in gamma-aminobutyric acid (GABA) ergic neurons exhibit spontaneous seizures and high premature mortality due to increased presynaptic release, postsynaptic potential, neuronal excitability, and synaptic transmission in hippocampal dentate gyrus granule cells (DGGCs). Attenuating early excitatory gamma-aminobutyric acid (GABA) action by administering bumetanide, an inhibitor of early GABA depolarization, rescued premature mortality. Rbfox3 deletion reduced hippocampal expression of vesicle-associated membrane protein 1 (VAMP1), a GABAergic neuron-specific presynaptic protein. Postnatal restoration of VAMP1 rescued premature mortality and neuronal excitability in DGGCs. Furthermore, Rbfox3 deletion in GABAergic neurons showed fewer neuropeptide Y (NPY)-expressing GABAergic neurons. In addition, deletion of Rbfox3 in NPY-expressing GABAergic neurons lowered intrinsic excitability and increased seizure susceptibility. Our results establish RBFOX3 as a critical regulator and possible treatment path for epilepsy.

The norepinephrine-releasing neurons in the locus coeruleus (LC) are well known to regulate wakefulness/arousal. They display active firing during wakefulness and a decreased discharge rate during sleep. We have previously reported that LC neurons express large numbers of GABA B receptors (GABA B Rs) located at peri-/extrasynaptic sites and are subject to tonic inhibition due to the continuous activation of GABA B Rs by ambient GABA, which is significantly higher during sleep than during wakefulness. In this study, we further showed using western blot analysis that the activation of GABA B Rs with baclofen could increase the level of phosphorylated extracellular signal-regulated kinase 1 (ERK 1 ) in LC tissue. Recordings from LC neurons in brain slices showed that the inhibition of ERK 1/2 with U0126 and FR180204 accelerated the decay of whole-cell membrane current induced by prolonged baclofen application. In addition, the inhibition of ERK 1/2 also increased spontaneous firing and reduced tonic inhibition of LC neurons after prolonged exposure to baclofen. These results suggest a new role of GABA B Rs in mediating ERK 1 -dependent autoregulation of the stability of GABA B R-activated whole-cell current, in addition to its well-known effect on gated potassium channels, to cause a tonic current in LC neurons.

Quantitative depth of a subjective occluding surface could only be perceived when binocularly matched information is presented along with temporal interocular unmatched (IOUM) information [1]. However, it is still unclear whether the horizontal separation that binocularly matched information is presented from the occluding surface edge would affect the quantitative depth perception. In the present study we aim to answer this question by manipulating the distance between binocularly matched and IOUM information in spatial domains. In Experiment 1, we examined the spatial limitation of binocular matched information along horizontal axes by measuring the threshold for quantitatively perceiving depth from temporal interocular asynchrony. In Experiment 2, within the threshold, temporal IOUM information was presented at three distances from the matched information along horizontal axes, respectively. Our results from these experiments showed a robust effect of binocular information in generating quantitative perceived depth from IOUM information in spatial domains. Moreover, the perceived depth of the subjective surface can be significantly influenced by spatial separations along horizontal axes. This may help to propose a computational theory of the mechanisms underlying "da Vinci stereopsis" in motion and other stereoscopic percepts.

Aim: To explore hemodynamics and vasoactive substance levels during renal vein congestion that occurs in the anhepatic phase of liver transplantation., Methods: New Zealand rabbits received ligation of the hepatic pedicle, supra-hepatic vena cava and infra-hepatic vena cava [anhepatic phase group (APH); n = 8], the renal veins (RVL; n = 8), renal veins and hepatic pedicle [with the inferior vena cava left open) (RVHP; n = 8)], or a sham operation (SOP; n = 8). Hemodynamic parameters (systolic, diastolic, and mean arterial blood pressures) and the levels of serum bradykinin (BK) and angiotensin II (ANGII) were measured at baseline (0 min), and 10 min, 20 min, 30 min, and 45 min after the surgery. Correlation analyses were performed to evaluate the associations between hemodynamic parameters and levels of vasoactive substances., Results: All experimental groups (APH, RVL, and RVHP) showed significant decreases in hemodynamic parameters (systolic, diastolic, and mean arterial blood pressures) compared to baseline levels, as well as compared to the SOP controls (P < 0.05 for all). In contrast, BK levels were significantly increased compared to baseline in the APH, RVL, and RVHP groups at all time points measured (P < 0.05 for all), whereas no change was observed in the SOP controls. There were no significant differences among the experimental groups for any measure at any time point. Further analyses revealed that systolic, diastolic, and mean arterial blood pressures were all negatively correlated with BK levels, and positively correlated with ANGII levels in the APH, RVL, and RVHP groups (P < 0.05 for all)., Conclusion: In the anhepatic phase of orthotopic liver transplantation, renal vein congestion significantly impacts hemodynamic parameters, which correlate with serum BK and ANGII levels.

To investigate the role of mechanical pressure on cartilage thickness and type II collagen synthesis, and the role of G protein in that process, in vitro organ culture of mandibular cartilage was adopted in this study. A hydraulic pressure-controlled cellular strain unit was used to apply hydrostatic pressurization to explant cultures. The explants were compressed by different pressure values (0 kPa, 100 kPa, and 300 kPa) after pretreatment with or without a selective and direct antagonist (NF023) for the G proteins. After 4, 8 and 12 h of cell culture under each pressure condition, histological sections of the explants were stained with hematoxylin-eosin to investigate the thickness of the cartilage. Immunohistochemical staining was used to observe type II collagen expressions. The results showed that a hydrostatic pressure of 100 kPa significantly reduced the thickness of the proliferative layer in condylar cartilage without affecting the thickness of the transitional layer. Hydrostatic pressures of 100 kPa and 300 kPa significantly enhanced the synthesis of type II collagen. G proteins are involved not only in the proliferation and differentiation of condylar cartilage regulated by prolonged pressure, but also in the process of collagen production in condylar cartilage stimulated by pressure.