Multiple and plastic receptors mediate tonic GABAA receptor currents in the hippocampus

Persistent activation of GABAA receptors by extracellular GABA (tonic inhibition) plays a critical role in signal processing and network excitability in the brain. In hippocampal principal cells, tonic inhibition has been reported to be mediated by {alpha}5-subunit-containing GABAA receptors ({alpha}5GABAARs). Pharmacological or genetic disruption of these receptors improves cognitive performance, suggesting that tonic inhibition has an adverse effect on information processing. Here, we show that {alpha}5GABAARs contribute to tonic currents in pyramidal cells only when ambient GABA concentrations increase (as may occur during increased brain activity). At low ambient GABA concentrations, activation of {delta}-subunit-containing GABAA receptors predominates. In epileptic tissue, {alpha}5GABAARs are downregulated and no longer contribute to tonic currents under conditions of raised extracellular GABA concentrations. Under these conditions, however, the tonic current is greater in pyramidal cells from epileptic tissue than in pyramidal cells from nonepileptic tissue, implying substitution of {alpha}5GABAARs by other GABAA receptor subtypes. These results reveal multiple components of tonic GABAA receptor-mediated conductance that are activated by low GABA concentrations. The relative contribution of these components changes after the induction of epilepsy, implying an adaptive plasticity of the tonic current in the presence of spontaneous seizures

Inclusive Brain: From Neuronal Doctrine to the Active Milieu

This work was supported by the Russian Foundation for Basic Research (RFBR), Grant No. 21-54-53018

Glial decline and loss of homeostatic support rather than inflammation defines cognitive aging

The work of AS was supported by the Russian Science Foundation, No. 20-14-00241

Experimental and theoretical study of light scattering by individual mature red blood cells by use of scanning flow cytometry and discrete dipole approximation

Elastic light scattering by mature red blood cells (RBCs) was theoretically and experimentally analyzed with the discrete dipole approximation (DDA) and the scanning flow cytometry (SFC), respectively. SFC permits measurement of angular dependence of light-scattering intensity (indicatrix) of single particles. A mature RBC is modeled as a biconcave disk in DDA simulations of light scattering. We have studied the effect of RBC orientation related to the direction of the incident light upon the indicatrix. Numerical calculations of indicatrices for several aspect ratios and volumes of RBC have been carried out. Comparison of the simulated indicatrices and indicatrices measured by SFC showed good agreement, validating the biconcave disk model for a mature RBC. We simulated the light-scattering output signals from the SFC with the DDA for RBCs modeled as a disk-sphere and as an oblate spheroid. The biconcave disk, the disk-sphere, and the oblate spheroid models have been compared for two orientations, i.e. face-on and rim-on incidence. Only the oblate spheroid model for rim-on incidence gives results similar to the rigorous biconcave disk model.Comment: 13 pages, 9 figure

Astrocytic Coverage of Dendritic Spines, Dendritic Shafts, and Axonal Boutons in Hippocampal Neuropil

Distal astrocytic processes have a complex morphology, reminiscent of branchlets and leaflets. Astrocytic branchlets are rod-like processes containing mitochondria and endoplasmic reticulum, capable of generating inositol-3-phosphate (IP3)-dependent Ca2+ signals. Leaflets are small and flat processes that protrude from branchlets and fill the space between synapses. Here we use three-dimensional (3D) reconstructions from serial section electron microscopy (EM) of rat CA1 hippocampal neuropil to determine the astrocytic coverage of dendritic spines, shafts and axonal boutons. The distance to the maximum of the astrocyte volume fraction (VF) correlated with the size of the spine when calculated from the center of mass of the postsynaptic density (PSD) or from the edge of the PSD, but not from the spine surface. This suggests that the astrocytic coverage of small and larger spines is similar in hippocampal neuropil. Diffusion simulations showed that such synaptic microenvironment favors glutamate spillover and extrasynaptic receptor activation at smaller spines. We used complexity and entropy measures to characterize astrocytic branchlets and leaflets. The 2D projections of astrocytic branchlets had smaller spatial complexity and entropy than leaflets, consistent with the higher structural complexity and less organized distribution of leaflets. The VF of astrocytic leaflets was highest around dendritic spines, lower around axonal boutons and lowest around dendritic shafts. In contrast, the VF of astrocytic branchlets was similarly low around these three neuronal compartments. Taken together, these results suggest that astrocytic leaflets preferentially contact synapses as opposed to the dendritic shaft, an arrangement that might favor neurotransmitter spillover and extrasynaptic receptor activation along dendritic shafts

The Anti-Inflammatory Astrocyte Revealed: the Role of the Microbiome in Shaping Brain Defences

Astrocytes are a sub-type of neuroglia responsible for homoeostasis and defence of the nervous system. Pathological reactions of neuroglial cells in various neurological disorders have been identified and characterised in the end of the 19th century; in particular hypertrophy of astrocytes was recognised as a frequent morbid change accompanying diseases of the central nervous system (CNS).This work was supported by grants of the National Key R&D Programme of China (2019YFC1709101) and the Project First-Class Disciplines Development of Chengdu University of Traditional Chinese Medicine (CZYHW1901) awarded in order to build up the “International Collaborative Centre on Big Science Plan for Purinergic Signalling”, and the Science and Technology Programme of Sichuan Province, China (2019YFH0108). The stay and work of PI in Chengdu was supported by a grant from the State Administration of Foreign Experts Affairs (G20190236012). A.S. and Y.T. are supported by RFBR grant 21-54-53018 for the NSFC-RFBR projec

Dopamine elevates and lowers astroglial Ca(2+) through distinct pathways depending on local synaptic circuitry

Whilst astrocytes in culture invariably respond to dopamine with cytosolic Ca(2+) rises, the dopamine sensitivity of astroglia in situ and its physiological roles remain unknown. To minimize effects of experimental manipulations on astroglial physiology, here we monitored Ca(2+) in cells connected via gap junctions to astrocytes loaded whole-cell with cytosolic indicators in area CA1 of acute hippocampal slices. Aiming at high sensitivity of [Ca(2+) ] measurements, we also employed life-time imaging of the Ca(2+) indicator Oregon Green BAPTA-1. We found that dopamine triggered a dose-dependent, bidirectional Ca(2+) response in stratum radiatum astroglia, a jagged elevation accompanied and followed by below-baseline decreases. The elevation depended on D1/D2 receptors and engaged intracellular Ca(2+) storage and removal whereas the dopamine-induced [Ca(2+) ] decrease involved D2 receptors only and was sensitive to Ca(2+) channel blockade. In contrast, the stratum lacunosum moleculare astroglia generated higher-threshold dopamine-induced Ca(2+) responses which did not depend on dopamine receptors and were uncoupled from the prominent inhibitory action of dopamine on local perforant path synapses. Our findings thus suggest that a single neurotransmitter-dopamine-could either elevate or decrease astrocyte [Ca(2+) ] depending on the receptors involved, that such actions are specific to the regional neural circuitry and that they may be causally uncoupled from dopamine actions on local synapses. The results also indicate that [Ca(2+) ] elevations commonly detected in astroglia can represent the variety of distinct mechanisms acting on the microscopic scale. GLIA 2016