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Nicotine induces intracellular Ca2+ increases in cultured hippocampal astrocytes by nAChR-dependent and -independent pathways  [PDF]
Miriam Hernández-Morales, Jesús García-Colunga
World Journal of Neuroscience (WJNS) , 2014, DOI: 10.4236/wjns.2014.41005

Nicotine, the major addictive substance in tobacco, interacts with nicotinic acetylcholine receptors (nAChRs) located in neuronal and glial cells, modulating synaptic transmission and memory. Here, we show that nAChRs agonists, including nicotine, acetylcholine, and choline, increase the intracellular Ca2+ concentration ([Ca2+]i) in cultured hippocampal astrocytes, indicating the involvement of nAChRs. Interestingly, inhibition of nAChRs, with a cocktail of antagonists (mecamylamine, methyllycaconitine plus dihydro-β- erythroidine), does not prevent the astrocytic [Ca2+]i increases generated by nicotine. This last effect would be attributable to inhibition of K+ currents by nicotine in these cells, as previously we showed using patch- clamp recordings. Furthermore, the application of tetraethylammonium, an inhibitor of K+ currents, also increases the [Ca2+]i. Together, these results indicate that nicotine increases [Ca2+]i in hippocampal astrocytes through two pathways: by activation of nAChRs, and likely by direct inhibition of K+ currents.

Nicotine Elicits Prolonged Calcium Signaling along Ventral Hippocampal Axons  [PDF]
Chongbo Zhong, David A. Talmage, Lorna W. Role
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0082719
Abstract: Presynaptic nicotinic acetylcholine receptors (nAChRs) have long been implicated in the modulation of CNS circuits. We previously reported that brief exposure to low concentrations of nicotine induced sustained potentiation of glutamatergic transmission at ventral hippocampal (vHipp)-striatal synapses. Here, we exploited nAChR subtype-selective antagonists and agonists and α7*nAChR knockout mutant mice (α7-/-) to elucidate the signaling mechanisms underlying nAChR-mediated modulation of synaptic transmission. Using a combination of micro-slices culture from WT and α7-/-mice, calcium imaging, and immuno-histochemical techniques, we found that nicotine elicits localized and oscillatory increases in intracellular Ca2+ along vHipp axons that persists for up to 30 minutes. The sustained phase of the nicotine-induced Ca2+ response was blocked by α-BgTx but not by DHβE and was mimicked by α7*nAChR agonists but not by non-α7*nAChR agonists. In vHipp slices from α7-/- mice, nicotine elicited only transient increases of axonal Ca2+ signals and did not activate CaMKII. The sustained phase of the nicotine-induced Ca2+ response required localized activation of CaMKII, phospholipase C, and IP3 receptor mediated Ca2+-induced Ca2+ release (CICR). In conclusion, activation of presynaptic nAChRs by nicotine elicits Ca2+ influx into the presynaptic axons, the sustained phase of the nicotine-induced Ca2+ response requires that axonal α7*nAChR activate a downstream signaling network in the vHipp axons.
Modulation of synchronous calcium oscillations in hippocampal neurons by photostimulation of astrocytes with femtosecond laser
Yuan Zhao,XiuLi Liu,Yuan Zhang,Wei Zhou,ShaoQun Zeng
Chinese Science Bulletin , 2010, DOI: 10.1007/s11434-010-3376-z
Abstract: A large body of evidence indicates that astrocytes play an important role in a range of brain functions through calcium (Ca2+) signaling. Experimentally evoking Ca2+ signaling is a useful technique for investigating the functions of astrocytes. However, conventional stimulation methods typically have poor spatio-temporal precision, and some are invasive. Our group has developed a technique to overcome these problems, in which astrocytes are photostimulated with a femtosecond laser. In the current study, we applied this method to a hippocampal neural network to explore astrocytic functions in detail. The results revealed that applying photostimulation to astrocytes in a cultured hippocampal astrocyte-neuron network caused the following changes: (i) Synchronous Ca2+ oscillations in neurons were induced; (ii) spontaneous Ca2+ synchrony instantaneously emerged; and (iii) high-frequency spontaneous Ca2+ synchrony was regulated. Thus, astrocytic Ca2+ signaling evoked by photostimulation was found to modulate synchronous Ca2+ oscillations in hippocampal neurons. We propose that photostimulation with a femtosecond laser will serve as a powerful tool in investigating astrocytic functions at the network level.
GABA release by hippocampal astrocytes  [PDF]
Juan Mendizabal-Zubiaga,Pedro Grandes,Etienne Audinat
Frontiers in Computational Neuroscience , 2012, DOI: 10.3389/fncom.2012.00059
Abstract: Astrocytes can directly influence neuronal activity through the release of various transmitters acting on membrane receptors expressed by neurons. However, in contrast to glutamate and ATP for instance, the release of GABA (γ-amino-butyric acid) by astrocytes is still poorly documented. Here, we used whole-cell recordings in rat acute brain slices and electron microscopy to test whether hippocampal astrocytes release the inhibitory transmitter GABA. We observed that slow transient inhibitory currents due to the activation of GABAA receptors occur spontaneously in principal neurons of the three main hippocampal fields (CA1, CA3, and dentate gyrus). These currents share characteristics with the slow NMDA receptor-mediated currents previously shown to result from astrocytic glutamate release: they occur in the absence of synaptic transmission and have variable kinetics and amplitudes as well as low frequencies. Osmotic pressure reduction, known to enhance transmitter release from astrocytes, similarly increased the frequency of non-synaptic GABA and glutamate currents. Simultaneous occurrence of slow inhibitory and excitatory currents was extremely rare. Yet, electron microscopy examination of immunostained hippocampal sections shows that about 80% of hippocampal astrocytes [positive for glial fibrillary acidic protein (GFAP)] were immunostained for GABA. Our results provide quantitative characteristics of the astrocyte-to-neuron GABAergic signaling. They also suggest that all principal neurons of the hippocampal network are under a dual, excitatory and inhibitory, influence of astrocytes. The relevance of the astrocytic release of GABA, and glutamate, on the physiopathology of the hippocampus remains to be established.
Sustained Na+/H+ Exchanger Activation Promotes Gliotransmitter Release from Reactive Hippocampal Astrocytes following Oxygen-Glucose Deprivation  [PDF]
Pelin Cengiz, Douglas B. Kintner, Vishal Chanana, Hui Yuan, Erinc Akture, Pinar Kendigelen, Gulnaz Begum, Emin Fidan, Kutluay Uluc, Peter Ferrazzano, Dandan Sun
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0084294
Abstract: Hypoxia ischemia (HI)-related brain injury is the major cause of long-term morbidity in neonates. One characteristic hallmark of neonatal HI is the development of reactive astrogliosis in the hippocampus. However, the impact of reactive astrogliosis in hippocampal damage after neonatal HI is not fully understood. In the current study, we investigated the role of Na+/H+ exchanger isoform 1 (NHE1) protein in mouse reactive hippocampal astrocyte function in an in vitro ischemia model (oxygen/glucose deprivation and reoxygenation, OGD/REOX). 2 h OGD significantly increased NHE1 protein expression and NHE1-mediated H+ efflux in hippocampal astrocytes. NHE1 activity remained stimulated during 1–5 h REOX and returned to the basal level at 24 h REOX. NHE1 activation in hippocampal astrocytes resulted in intracellular Na+ and Ca2+ overload. The latter was mediated by reversal of Na+/Ca2+ exchange. Hippocampal astrocytes also exhibited a robust release of gliotransmitters (glutamate and pro-inflammatory cytokines IL-6 and TNFα) during 1–24 h REOX. Interestingly, inhibition of NHE1 activity with its potent inhibitor HOE 642 not only reduced Na+ overload but also gliotransmitter release from hippocampal astrocytes. The noncompetitive excitatory amino acid transporter inhibitor TBOA showed a similar effect on blocking the glutamate release. Taken together, we concluded that NHE1 plays an essential role in maintaining H+ homeostasis in hippocampal astrocytes. Over-stimulation of NHE1 activity following in vitro ischemia disrupts Na+ and Ca2+ homeostasis, which reduces Na+-dependent glutamate uptake and promotes release of glutamate and cytokines from reactive astrocytes. Therefore, blocking sustained NHE1 activation in reactive astrocytes may provide neuroprotection following HI.
Active Sulforhodamine 101 Uptake into Hippocampal Astrocytes  [PDF]
Christian Schnell, Yohannes Hagos, Swen Hülsmann
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0049398
Abstract: Sulforhodamine 101 (SR101) is widely used as a marker of astrocytes. In this study we investigated labeling of astrocytes by SR101 in acute slices from the ventrolateral medulla and the hippocampus of transgenic mice expressing EGFP under the control of the astrocyte-specific human GFAP promoter. While SR101 efficiently and specifically labeled EGFP-expressing astrocytes in hippocampus, we found that the same staining procedure failed to label astrocytes efficiently in the ventrolateral medulla. Although carbenoxolone is able to decrease the SR101-labeling of astrocytes in the hippocampus, it is unlikely that SR101 is taken up via gap-junction hemichannels because mefloquine, a blocker for pannexin and connexin hemichannels, was unable to prevent SR101-labeling of hippocampal astrocytes. However, SR101-labeling of the hippocampal astrocytes was significantly reduced by substrates of organic anion transport polypeptides, including estron-3-sulfate and dehydroepiandrosterone sulfate, suggesting that SR101 is actively transported into hippocampal astrocytes.
Disruption in Connexin-Based Communication Is Associated with Intracellular Ca2+ Signal Alterations in Astrocytes from Niemann-Pick Type C Mice  [PDF]
Pablo J. Sáez, Juan A. Orellana, Natalia Vega-Riveros, Vania A. Figueroa, Diego E. Hernández, Juan F. Castro, Andrés D. Klein, Jean X. Jiang, Silvana Zanlungo, Juan C. Sáez
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0071361
Abstract: Reduced astrocytic gap junctional communication and enhanced hemichannel activity were recently shown to increase astroglial and neuronal vulnerability to neuroinflammation. Moreover, increasing evidence suggests that neuroinflammation plays a pivotal role in the development of Niemann-Pick type C (NPC) disease, an autosomal lethal neurodegenerative disorder that is mainly caused by mutations in the NPC1 gene. Therefore, we investigated whether the lack of NPC1 expression in murine astrocytes affects the functional state of gap junction channels and hemichannels. Cultured cortical astrocytes of NPC1 knock-out mice (Npc1?/?) showed reduced intercellular communication via gap junctions and increased hemichannel activity. Similarly, astrocytes of newborn Npc1?/? hippocampal slices presented high hemichannel activity, which was completely abrogated by connexin 43 hemichannel blockers and was resistant to inhibitors of pannexin 1 hemichannels. Npc1?/? astrocytes also showed more intracellular Ca2+ signal oscillations mediated by functional connexin 43 hemichannels and P2Y1 receptors. Therefore, Npc1?/? astrocytes present features of connexin based channels compatible with those of reactive astrocytes and hemichannels might be a novel therapeutic target to reduce neuroinflammation in NPC disease.
Nicotine Attenuates Activation of Tissue Resident Macrophages in the Mouse Stomach through the β2 Nicotinic Acetylcholine Receptor  [PDF]
Andrea Nemethova, Klaus Michel, Pedro J. Gomez-Pinilla, Guy E. Boeckxstaens, Michael Schemann
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0079264
Abstract: Background The cholinergic anti-inflammatory pathway is an endogenous mechanism by which the autonomic nervous system attenuates macrophage activation via nicotinic acetylcholine receptors (nAChR). This concept has however not been demonstrated at a cellular level in intact tissue. To this end, we have studied the effect of nicotine on the activation of resident macrophages in a mouse stomach preparation by means of calcium imaging. Methods Calcium transients ([Ca2+]i) in resident macrophages were recorded in a mouse stomach preparation containing myenteric plexus and muscle layers by Fluo-4. Activation of macrophages was achieved by focal puff administration of ATP. The effects of nicotine on activation of macrophages were evaluated and the nAChR involved was pharmacologically characterized. The proximity of cholinergic nerves to macrophages was quantified by confocal microscopy. Expression of β2 and α7 nAChR was evaluated by β2 immunohistochemistry and fluorophore-tagged α-bungarotoxin. Results In 83% of macrophages cholinergic varicose nerve fibers were detected at distances <900nm. The ATP induced [Ca2+]i increase was significantly inhibited in 65% or 55% of macrophages by 100μM or 10μM nicotine, respectively. This inhibitory effect was reversed by the β2 nAChR preferring antagonist dihydro-β-eryhtroidine but not by hexamethonium (non-selective nAChR-antagonist), mecamylamine (α3β4 nAChR-preferring antagonist), α-bungarotoxin or methyllycaconitine (both α7 nAChR-preferring antagonist). Macrophages in the stomach express β2 but not α7 nAChR at protein level, while those in the intestine express both receptor subunits. Conclusion This study is the first in situ demonstration of an inhibition of macrophage activation by nicotine suggesting functional signaling between cholinergic neurons and macrophages in the stomach. The data suggest that the β2 subunit of the nAChR is critically involved in the nicotine-induced inhibition of these resident macrophages.
Investigating the synchronization of hippocampal neural network in response to acute nicotine exposure
David Akkurt, Yasemin M Akay, Metin Akay
Journal of NeuroEngineering and Rehabilitation , 2010, DOI: 10.1186/1743-0003-7-31
Abstract: Using the approximate entropy method, the influence of acute nicotine exposure on the hippocampal γ oscillations was investigated. The hippocampal γ oscillations have been generated in response to the 100 Hz stimulus and isolated using the visual inspection and spectral analysis method. Our central hypothesis is that acute exposure to nicotine significantly reduces the complexity of hippocampal γ oscillations. We used brain-slice recordings and the approximate entropy method to test this hypothesis. The approximate entropy (complexity) values of the hippocampal γ oscillations are estimated from the 14 hippocampal slices. Our results show that it takes at least 100 msec to see any hippocampal activities in response to the 100 Hz stimulus. These patterns noticeably changed after 100 msec until 300 msec after the stimulus Finally, they were less prominent after 300 msec. We have analyzed the isolated hippocampal γ oscillations (between 150 and 250 msec after the stimulus) using the approximate entropy (ApEn) method. Our results showed that the ApEn (complexity) values of hippocampal γ oscillations during nicotine exposure were reduced compared to those of hippocampal γ oscillations during control, and washout. This reduction was much more significant in response to acute nicotine exposure (p < 0.05) compared to those during control and washout conditions. These results suggest that the neural firing becomes regular and the hippocampal networks become synchronized in response to nicotine exposure.Nicotine, C10H14N2, a tertiary amine compound, is a very toxic, light yellow alkaloid which is produced in tobacco plants as a result of the leaves' being damaged [1,2]. The roots of the damaged plants synthesize nicotine as a reaction to hormones released by the damaged tissue and then transport it to the leaves. Nicotine is stored in concentrations of 2-8 percent by weight in the leaves which becomes the primary psychoactive ingredient in tobacco smoke. It is very soluble in
A Mathematical model for Astrocytes mediated LTP at Single Hippocampal Synapses  [PDF]
Shivendra Tewari,Kaushik Majumdar
Quantitative Biology , 2011, DOI: 10.1007/s10827-012-0389-5
Abstract: Many contemporary studies have shown that astrocytes play a significant role in modulating both short and long form of synaptic plasticity. There are very few experimental models which elucidate the role of astrocyte over Long-term Potentiation (LTP). Recently, Perea & Araque (2007) demonstrated a role of astrocytes in induction of LTP at single hippocampal synapses. They suggested a purely pre-synaptic basis for induction of this N-methyl-D- Aspartate (NMDA) Receptor-independent LTP. Also, the mechanisms underlying this pre-synaptic induction were not investigated. Here, in this article, we propose a mathematical model for astrocyte modulated LTP which successfully emulates the experimental findings of Perea & Araque (2007). Our study suggests the role of retrograde messengers, possibly Nitric Oxide (NO), for this pre-synaptically modulated LTP.
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