Interhemispheric sleep EEG asymmetry in the rat is enhanced by sleep deprivation

Vigilance state-related topographic variations of electroencephalographic (EEG) activity have been reported in humans and animals. To investigate their possible functional significance, the cortical EEG of the rat was recorded from frontal and parietal derivations in both hemispheres. Records were obtained for a 24-h baseline day, 6-h sleep deprivation (SD), and subsequent 18-h recovery. During the baseline 12-h light period, the main sleep period of the rat, low-frequency (<7.0 Hz) power in the non-rapid eye-movement (NREM) sleep EEG declined progressively. Left-hemispheric predominance of low-frequency power at the parietal derivations was observed at the beginning of the light period when sleep pressure is high due to preceding spontaneous waking. The left-hemispheric dominance changed to a right-hemispheric dominance in the course of the 12-h rest-phase when sleep pressure dissipated. During recovery from SD, both low-frequency power and parietal left-hemispheric predominance were enhanced. The increase in low-frequency power in NREM sleep observed after SD at the frontal site was larger than at the parietal site. However, frontally no interhemispheric differences were present. In REM sleep, power in the theta band (5.25-8.0 Hz) exhibited a right-hemispheric predominance. In contrast to NREM sleep, the hemispheric asymmetry showed no trend during baseline and was not affected by SD. Use-dependent local changes may underlie the regional differences in the low-frequency NREM sleep EEG within and between hemispheres. The different interhemispheric asymmetries in NREM and REM sleep suggest that the two sleep states may subserve different functions in the brain.     

Exome sequencing in familial corticobasal degeneration

BackgroundCorticobasal degeneration (CBD) is a neurodegenerative, sporadic disorder of unknown cause. Few familial cases have been described.ObjectiveWe aim to characterize the clinical, imaging, pathological and genetic features of two familial cases of CBD.MethodsWe describe two first cousins with CBD associated with atypical MRI findings. We performed exome sequencing in both subjects and in an unaffected first cousin of similar age.ResultsThe cases include a 79-year-old woman and a 72-year-old man of Native American and British origin. The onset of the neurological manifestations was 74 and 68 years respectively. Both patients presented with a combination of asymmetric parkinsonism, apraxia, myoclonic tremor, cortical sensory syndrome, and gait disturbance. The female subject developed left side fixed dystonia. The manifestations were unresponsive to high doses of levodopa in both cases. Extensive bilateral T1-W hyperintensities and T2-W hypointensities in basal ganglia and thalamus were observed in the female patient; whereas these findings were more subtle in the male subject. Postmortem examination of both patients was consistent with corticobasal degeneration; the female patient had additional findings consistent with mild Alzheimer's disease. No Lewy bodies were found in either case. Exome sequencing showed mutations leading to possible structural changes in MRS2 and ZHX2 genes, which appear to have the same upstream regulator miR-4277.ConclusionsCorticobasal degeneration can have a familial presentation; the role of MRS2 and ZHX2 gene products in CBD should be further investigated.     

Sleep EEG in mice that are deficient in the potassium channel subunit K.v.3.2

Voltage-gated potassium channels containing the K.v.3.2 subunit are expressed in specific neuronal populations such as thalamocortical neurons and fast spiking GABAergic interneurons of the neocortex and hippocampus. These K(+)-channels play a major role in the regulation of firing properties in these neurons. We investigated whether the K.v.3.2 subunit contributes to the generation of the sleep electroencephalogram (EEG). The EEG of a frontal and occipital derivation of K.v.3.2-deficient mice and littermate controls was recorded during a 24-h baseline, 6-h sleep deprivation (SD) and subsequent 18-h recovery to assess also the effects of the K.v.3.2 subunit deficiency under physiological sleep pressure. The K.v.3.2-deficient mice had lower EEG power density in the frequencies between 3.25 and 6 Hz in nonREM (NREM) sleep and 3.25-5 Hz in REM sleep. These differences were more prominent in the frontal derivation than in the occipital derivation. The waking EEG spectrum was not affected by the deletion. In both genotypes SD induced a prominent increase in slow-wave activity in NREM sleep (mean EEG power density between 0.75 and 4.0 Hz), and a concomitant decrease in sleep fragmentation. The effects of SD did not differ significantly between the genotypes. The results indicate that K.v.3.2 channels may be involved in the generation of EEG oscillations in the high delta and low theta range in sleep. They support the notion that GABA-mediated synchronization of cortical activity contributes to the electroencephalogram.     

Highly chlorinated PCBs inhibit the human xenobiotic response mediated by the steroid and xenobiotic receptor (SXR)

Polychlorinated biphenyls (PCBs) are a family of persistent organic contaminants suspected to cause adverse effects in wildlife and humans. In rodents, PCBs bind to the aryl hydrocarbon (AhR) and pregnane X receptors (PXR) inducing the expression of catabolic cytochrome p450 enzymes of the CYP1A and 3A families. We found that certain highly chlorinated PCBs are potent activators of rodent PXR but antagonize its human ortholog, the steroid and xenobiotic receptor (SXR), inhibiting target gene induction. Thus, exposure to PCBs may blunt the human xenobiotic response, inhibiting the detoxification of steroids, bioactive dietary compounds, and xenobiotics normally mediated by SXR. The antagonistic PCBs are among the most stable and abundant in human tissues. These findings have important implications for understanding the biologic effects of PCB exposure and the use of animal models to predict the attendant risk.     

The EEG effects of THIP (Gaboxadol) on sleep and waking are mediated by the GABA(A)delta-subunit-containing receptors

THIP (4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridine-3-ol, Gaboxadol) is a selective gamma-aminobutyric acid (GABA)(A) agonist, acting in vitro with high potency and efficacy at the extrasynaptic GABA(A)delta-containing receptors. THIP was suggested to be a potential hypnotic to treat insomnia, and it is currently in clinical trial. Here we assessed whether the GABA(A)delta-containing receptors mediate in vivo the effect of THIP on sleep and the sleep electroencephalogram (EEG). We performed EEG recordings in a mouse model deficient in the GABA(A)delta-subunit gene (delta(-/-) mice) and in wild-type littermate controls. THIP (4 and 6 mg/kg intraperitoneally) induced an abnormal EEG pattern, resulting in dramatic changes in the waking and non-rapid eye movement (NREM) sleep EEG spectra in wild-type mice. Indeed, a massive increase in EEG power lasting 2-3 h occurred in both the frontal and parietal derivation, especially in frequencies below 6 Hz. All effects were more prominent in the frontal EEG. Furthermore, the highest dose of THIP lengthened REM sleep latency and suppressed REM sleep. In contrast, vigilance states and sleep latencies were not affected in delta(-/-) mice. Moreover, only minor changes were observed in the NREM sleep EEG spectrum after THIP injection in the delta-subunit-deficient mice. The present findings do not indicate a sleep-promoting effect of THIP in mice, which is in accordance with a previous report in this species. Moreover, our results in vivo demonstrate that THIP acts preferentially at GABA(A) receptors containing the delta-subunit.     

An obligatory requirement for the heterotrimeric G protein Gi3 in the antiautophagic action of insulin in the liver

Heterotrimeric G proteins of the G(i) class have been implicated in signaling pathways regulating growth and metabolism under physiological and pathophysiological conditions. Knockout mice carrying inactivating mutations in both of the widely expressed Galpha(i) class genes, Galpha(i2) and Galpha(i3), demonstrate shared as well as gene-specific functions. The presence of a single active allele of Galpha(i3) is sufficient for embryonic development, whereas at least one allele of Galpha(i2) is required for extrauterine life. Mice lacking both Galpha(i2) and Galpha(i3) are massively growth-retarded and die in utero. We have used biochemical and cell biological methods together with in situ liver perfusion experiments to study Galpha(i) isoform-specific functions in Galpha(i2)- and Galpha(i3)-deficient mice. The subcellular localization of Galpha(i3) in isolated mouse hepatocytes depends on the cellular metabolic status. Galpha(i3) localizes to autophagosomes upon starvation-induced autophagy and distributes to the plasma membrane upon insulin stimulation. Analysis of autophagic proteolysis in perfused mouse livers showed that mice lacking Galpha(i3) are deficient in the inhibitory action of insulin. These data indicate that Galpha(i3) is crucial for the antiautophagic action of insulin and suggest an as-yet-unrecognized function for Galpha(i3) on autophagosomal membranes.