Recent studies implicate astrocytes in Alzheimer’s disease (AD); however, their role in pathogenesis is poorly understood. Astrocytes have well-established functions in supportive functions such as extracellular ionic homeostasis, structural support, and neurovascular coupling. However, emerging research on astrocytic function in the healthy brain also indicates their role in regulating synaptic plasticity and neuronal excitability via the release of neuroactive substances named gliotransmitters. Here, we review how this “active” role of astrocytes at synapses could contribute to synaptic and neuronal network dysfunction and cognitive impairment in AD.

Alzheimer's disease (AD) is associated with senile plaques of beta-amyloid (Aβ) that affect the function of neurons and astrocytes. Brain activity results from the coordinated function of neurons and astrocytes in astroglial-neuronal networks. However, the effects of Aβ on astroglial and neuronal network function remains unknown.Simultaneously monitoring astrocyte calcium and electric neuronal activities, we quantified the impact of Aβ on sensory-evoked cortical activity in a mouse model of AD. At rest, cortical astrocytes displayed spontaneous hyperactivity that was related to Aβ density. Sensory-evoked astrocyte responsiveness was diminished in AD mice, depending on the density and distance of Aβ, and the responses showed altered calcium dynamics. Hence, astrocytes were spontaneously hyperactive but hyporesponsive to sensory stimulation. Finally, AD mice showed sensory-evoked electrical cortical hyperresponsiveness associated with altered astrocyte-neuronal network interplay. Our findings suggest dysfunction of astrocyte networks in AD mice may dysregulate cortical electrical activity and contribute to cognitive decline.

We characterized the ionic currents underlying the cellular excitability and the Ca 2+ -channel subtypes involved in action potential (AP) firing of rat adrenal chromaffin cells (RCCs) preserved in their natural environment, the adrenal gland slices, through the perforated patch-clamp recording technique. RCCs prepared from adrenal slices exhibit a resting potential of À54 mV, firing spontaneous APs (2-3 spikes/s) generated by the opening of Na + and Ca 2+ -channels, and terminated by the activation of voltage and Ca-channels is involved in reaching threshold potential for AP firing, and is responsible for activation of BK-channels contributing to APrepolarization and afterhyperpolarization, whereas P/Q-type Ca 2+ -channels are involved only in the repolarization phase. BK-channels carry total outward current during AP-repolarization. Blockade of L-type Ca 2+ -channels reduces BK-current 60%, whereas blockade of N-or P/Q-type produces little effect. This study demonstrates that Ca 2+ influx through L-type Ca 2+ -channels plays a key role in modulating the threshold potential from RCCs in situ.

It is currently known that in CNS the extracellular matrix is involved in synaptic stabilization and limitation of synaptic plasticity. However, it has been reported that the treatment with chondroitinase following injury allows the formation of new synapses and increased plasticity and functional recovery. So, we hypothesize that some components of extracellular matrix may modulate synaptic transmission. To test this hypothesis we evaluated the effects of chondroitin sulphate (CS) on excitatory synaptic transmission, cellular excitability, and neuronal plasticity using extracellular recordings in the CA1 area of rat hippocampal slices. CS caused a reversible depression of evoked field excitatory postsynaptic potentials in a concentration-dependent manner. CS also reduced the population spike amplitude evoked after orthodromic stimulation but not when the population spikes were antidromically evoked; in this last case a potentiation was observed. CS also enhanced paired-pulse facilitation and long-term potentiation. Our study provides evidence that CS, a major component of the brain perineuronal net and extracellular matrix, has a function beyond the structural one, namely, the modulation of synaptic transmission and neuronal plasticity in the hippocampus.

As the peripheral sympathoadrenal axis is tightly controlled by the cortex via hypothalamus and brain stem, the central pathological features of Hunting's disease, (HD) that is, deposition of mutated huntingtin and synaptic dysfunctions, could also be expressed in adrenal chromaffin cells. To test this hypothesis we here present a thorough investigation on the pathological and functional changes undergone by chromaffin cells (CCs) from 2-month (2 m) to 7-month (7 m) aged wild-type (WT) and R6/1 mouse model of Huntington's disease (HD), stimulated with acetylcholine (ACh) or high [K ] (K ). In order to do this, we used different techniques such as inmunohistochemistry, patch-clamp, and amperometric recording. With respect to WT cells, some of the changes next summarized were already observed in HD mice at a pre-disease stage (2 m); however, they were more pronounced at 7 m when motor deficits were clearly established, as follows: (i) huntingtin over-expression as nuclear aggregates in CCs; (ii) smaller CC size with decreased dopamine β-hydroxylase expression, indicating lesser number of chromaffin secretory vesicles; (iii) reduced adrenal tissue catecholamine content; (iv) reduced Na currents with (v) membrane hyperpolarization and reduced ACh-evoked action potentials; (v) reduced [Ca ] transients with faster Ca clearance; (vi) diminished quantal secretion with smaller vesicle quantal size; (vii) faster kinetics of the exocytotic fusion pore, pore expansion, and closure. On the basis of these data, the hypothesis is here raised in the sense that nuclear deposition of mutated huntingtin in adrenal CCs of R6/1 mice could be primarily responsible for poorer Na channel expression and function, giving rise to profound depression of cell excitability, altered Ca handling and exocytosis. OPEN PRACTICES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/. Cover Image for this issue: doi: 10.1111/jnc.14201.

Microcircuits in the neocortex are functionally organized along layers and columns, which are the fundamental modules of cortical information processing. While the function of cortical microcircuits has focused on neuronal elements, much less is known about the functional organization of astrocytes and their bidirectional interaction with neurons. Here, we show that Cannabinoid type 1 receptor (CB1R)-mediated astrocyte activation by neuron-released endocannabinoids elevate astrocyte Ca2+ levels, stimulate ATP/adenosine release as gliotransmitters, and transiently depress synaptic transmission in layer 5 pyramidal neurons at relatively distant synapses (˃20 μm) from the stimulated neuron. This astrocyte-mediated heteroneuronal synaptic depression occurred between pyramidal neurons within a cortical column and was absent in neurons belonging to adjacent cortical columns. Moreover, this form of heteroneuronal synaptic depression occurs between neurons located in particular layers, following a specific connectivity pattern that depends on a layer-specific neuron-to-astrocyte signaling. These results unravel the existence of astrocyte-mediated nonsynaptic communication between cortical neurons and that this communication is column- and layer-specific, which adds further complexity to the intercellular signaling processes in the neocortex.

Gasotransmitter hydrogen sulphide (HS) has emerged as a regulator of multiple physiological and pathophysiological processes throughout. Here, we have investigated the effects of NaHS (fast donor of HS) and GYY4137 (GYY, slow donor of HS) on the exocytotic release of catecholamines from fast-perifused bovine adrenal chromaffin cells (BCCs) challenged with sequential intermittent pulses of a K-depolarizing solution. Both donors caused a concentration-dependent facilitation of secretion. This was not due to an augmentation of Ca entry through voltage-activated Ca channels (VACCs) because, in fact, NaHS and GYY caused a mild inhibition of whole-cell Ca currents. Rather, the facilitation of exocytosis seemed to be associated to an augmented basal [Ca] and the K-elicited [Ca] transients; such effects of HS donors are aborted by cyclopiazonic acid (CPA), that causes endoplasmic reticulum (ER) Ca depletion through sarcoendoplasmic reticulum Ca2+ ATPase inhibition and by protonophore carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP), that impedes the ability of mitochondria to sequester cytosolic Ca during cell depolarization. Inasmuch as CPA and FCCP reversed the facilitation of secretion triggered by K in the presence of NaHS and GYY, is seems that such facilitation is tightly coupled to Ca handling by the ER and mitochondria. On the basis of these results, we propose that HS regulates catecholamine secretory responses triggered by K in BCCs by (i) mobilisation of ER Ca and (ii) interference with mitochondrial Ca circulation. In so doing, the clearance of the [Ca] transient will be delayed and the Ca-dependent trafficking of secretory vesicles will be enhanced to overfill the secretory machinery with new vesicles to enhance exocytosis.

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