12 research outputs found
Reduced brain levels of DHEAS in hepatic coma patients: significance for increased GABAergic tone in hepatic encephalopathy
Increased neurosteroids with allosteric modulatory activity on GABA A receptors such as 3α-5α tertrahydroprogesterone; allopregnanolone (ALLO), are candidates to explain the phenomenon of "increased GABAergic tone" in hepatic encephalopathy (HE). However, it is not known how changes of other GABA A receptor modulators such as dehydroepiandrosterone sulfate (DHEAS) contribute to altered GABAergic tone in HE. Concentrations of DHEAS were measured by radioimmunoassay in frontal cortex samples obtained at autopsy from 11 cirrhotic patients who died in hepatic coma and from an equal number of controls matched for age, gender, and autopsy delay intervals free from hepatic or neurological diseases. To assess whether reduced brain DHEAS contributes to increased GABAergic tone, in vitro patch clamp recordings in rat prefrontal cortex neurons were performed. A significant reduction of DHEAS (5.81 ± 0.88 ng/g tissue) compared to control values (9.70 ± 0.79 ng/g, p < 0.01) was found. Brain levels of DHEAS in patients with liver disease who died without HE (11.43 ± 1.74 ng/g tissue), and in a patient who died in uremic coma (12.56 ng/g tissue) were within the control range. Increasing ALLO enhances GABAergic tonic currents concentration-dependently, but increasing DHEAS reduces these currents. High concentrations of DHEAS (50 μM) reduce GABAergic tonic currents in the presence of ALLO, whereas reduced concentrations of DHEAS (1 μM) further stimulate these currents. These findings demonstrate that decreased concentrations of DHEAS together with increased brain concentrations of ALLO increase GABAergic tonic currents synergistically; suggesting that reduced brain DHEAS could further increase GABAergic tone in human HE. © 2012 Elsevier Ltd
Enhanced ethanol voluntary intake and decreased hippocampal neuronal excitability in c57bl/6j mice exposed to post-weaning social isolation
Enhanced sensitivity to ethanol-induced inhibition of LTP in CA1 pyramidal neurons of socially isolated C57BL/6J mice.
ETHANOL ACTIONS IN C57BL/6J EXPOSED TO SOCIAL ISOLATION: EFFECTS ON HIPPOCAMPAL PLASTICITY AND ROLE OF NEURACTIVE STEROIDS
Integrative approach to sporadic Alzheimer’s disease: deficiency of TYROBP in cerebral Aβ amyloidosis mouse normalizes clinical phenotype and complement subnetwork molecular pathology without reducing Aβ burden
Multiscale causal networks identify VGF as a key regulator of Alzheimer’s disease
To investigate the molecular foundation of sporadic Alzheimer’s disease (AD), Beckmann et al. constructed multiscale causal networks on a large human AD multi-omics dataset, detecting AD-associated networks and their top predicted regulator, VGF, with extensive validation in the 5xFAD mouse model