Transmission of nociceptive signalling and mechanisms underlying its modulation

Specific features of calcium signalling in neurons of the nociceptive system, in particular in primary afferent (dorsal root ganglion) and secondary dorsal horn spinal units, are described. The roles of different types of calcium channels and intracellular Ca stores (those of the mitochondria and endoplasmic reticulum) and interactions between these cellular structures in the norm and under pathological conditions (in particular in diabetic neuropathy) are discussed. Neirofiziologiya/Neurophysiology, Vol. 39, No. 6, pp. 493–497, November–December, 2007.     

Effects of Disrupting Calcium Homeostasis on Neuronal Maturation: Early Inhibition and Later Recovery

It has become increasingly clear that agents that disrupt calcium homeostasis may also be toxic to developing neurons. Using isolated primary neurons, we sought to understand the neurotoxicity of agents such as MK801 (which blocks ligand-gated calcium entry), BAPTA (which chelates intracellular calcium), and thapsigargin (TG; which inhibits the endoplasmic reticulum Ca²⁺-ATPase pump). Thus, E18 rat cortical neurons were grown for 1 day in vitro (DIV) and then exposed to vehicle (0.1% DMSO), MK801 (0.01–20 μM), BAPTA (0.1–20 μM), or TG (0.001–1 μM) for 24 h. We found that all three agents could profoundly influence early neuronal maturation (growth cone expansion, neurite length, neurite complexity), with the order of potency being MK801 < BAPTA < TG. We next asked if cultures exposed to these agents were able to re-establish their developmental program once the agent was removed. When we examined network maturity at 4 and 7 DIV, the order of recovery was MK801 > BAPTA > TG. Thus, mechanistically distinct ways of disrupting calcium homeostasis differentially influenced both short-term and long-term neuronal maturation. These observations suggest that agents that act by altering intracellular calcium and are used in obstetrics or neonatology may be quite harmful to the still-developing human brain.     

Caffeine-induced oscillations of the membrane potential inAplysia neurons

It has been found in culturedAplysia neurons, including L7 and L2–L6 neurons, that bath application of 40 mM caffeine evokes oscillations of the membrane potential (MP) with the amplitude of about 40 mV. The frequency of oscillations, on the crest of which action potentials (AP) arise, varied from 0.2 to 0.5 sec¹. The effect of caffeine was completely reversible. The MP waves demonstrated high sensitivity to membrane polarization: artificial depolarization increased the frequency of oscillations, while even subtle hyperpolarization resulted in a decrease in the frequency up to their complete disappearance. External application of CdCl₂ (1 mM), a nonspecific blocker of calcium channels, or ryanodine (50 μM, 20 min), release of Ca²⁻ from the intracellular stores, replacement of Ca²⁺ in the external medium by Mg²⁻, or Na⁺ by Li⁺, did not exert visible effect on the parameters of MP waves. It was concluded that Ca ions (changing of intracellular concentration of which is due to such processes as inward calcium current, ryanodine-sensitive caffeine-induced calcium release from the intracellular, stores, sodium-calcium exchange through the plasma membrane) do not play any significant part in generation of the MP waves. The most probable mechanism of caffeine-induced oscillations in the studied nerve cells is inhibition of voltage-activated outward potassium current and, as could be seen from our mathematical modeling, slowdown of inactivation of inward sodium current. It seems likely that these oscillations have a purely membrane origin. Neirofiziologiya/Neurophysiology, Vol. 32, No. 2, pp. 102–111, March–April, 2000.     

The actions of the neonicotinoid imidacloprid on cholinergic neurons of Drosophila melanogaster

The neonicotinoid insecticide imidacloprid is an agonist on insect nicotinic acetylcholine receptors (nAChRs). We utilised fura-2-based calcium imaging to investigate the actions of imidacloprid on cultured GFP-tagged cholinergic neurons from the third instar larvae of the genetic model organism Drosophila melanogaster. We demonstrate dose-dependent increases in intracellular calcium ([Ca²⁺]_i) in cholinergic neurons upon application of imidacloprid (10 nM–100 μM) that are blocked by nAChR antagonists mecamylamine (10 μM) and α-bungarotoxin (α-BTX, 1 μM). When compared to other (untagged) neurons, cholinergic neurons respond to lower concentrations of imidacloprid (10–100 nM) and exhibit larger amplitude responses to higher (1–100 μM) concentrations of imidacloprid. Although imidacloprid acts via nAChRs, increases in [Ca²⁺]_i also involve voltage-gated calcium channels (VGCCs) in both groups of neurons. Thus, we demonstrate that cholinergic neurons express nAChRs that are highly sensitive to imidacloprid, and demonstrate a role for VGCCs in amplifying imidacloprid-induced increases in [Ca²⁺]_i.     

Increased contribution of N-methyl-D-aspartate receptors to synaptic transmission inCA1 area of the rat hippocampus after short-term episodes of hypoxia/aglycemia

Effect of hypoxia/aglycemia episodes on excitatory postsynaptic currents (EPSC) evoked in pyramidal neurons of the rat hippocampalCA1 area by electrical stimulation of Schaffer collaterals was studied using voltage-clamp and intracellular perfusion techniques. By 60–80 min after a 10-min-long hypoxia/aglycemia episode, the EPSC amplitude increased and the EPSC decay was considerably slowed down, if compared with control. In contrast to control conditions, under which EPSC decay kinetics did not depend on the stimulus strength, hypoxia/aglycemia was followed by slowing down of the EPSC decay when stimulus intensity increased. The stimulus-dependent posthypoxic “slow” EPSC component was depressed both by D-(−)-2-amino-5-phosphonovaleric acid, an NMDA receptor blocker, and by 6-cyano-7-nitroquinoline-2,3-dion, a non-NMDA receptor blocker, which suggested possible polysynaptic origin of the above EPSC component. We suggest that short-term hypoxia/aglycemia transforms into an active state the NMDA receptors in the synapses of excitatory reccurrent collaterals of theCA1 hippocampal area, which had not functioned before. An increase in the intracellular calcium concentration from 1.5 to 5.0 mM resulted in the effect similar to that produced by hypoxia/aglycemia, which suggests that calcium channels play an important role in the mechanisms responsible for hypoxia-related activation of “silent” NMDA receptors.     

Calcium Channels in the Nuclear Envelope of Pyramidal Neurons of the Rat Hippocampus

As is known, an increase in the concentration of Са²⁺ in the nuclei of nerve cells leads to activation of genes responsible for the formation of long-lasting postsynaptic changes; mechanisms of memory and learning are based on such changes. The pathways necessary for the entry of calcium into the nuclei of hippocampal pyramidal neurons remained unstudied. Using a patch-clamp technique, we studied what types of calcium channels exist in the membranes of isolated nuclei of pyramidal neurons of the hippocampal СА1 area. In the inner nuclear membrane of these cells, we, for the first time, found inositol trisphosphate receptors (IP₃Rs) activated by inositol trisphosphate applied in the concentration of ≥0.1 μM. The conductivity of single channels of such receptors was, on average, 366 pS; these channels were permeable for both monovalent and bivalent cations. Our data indicate that the nuclear envelope of pyramidal neurons of the hippocampal СА1 area can play the role of the calcium store from which Са²⁺ enter the cell nucleus directly. Neirofiziologiya/Neurophysiology, Vol. 40, No. 4, pp. 288–292, July–August, 2008.     

Inhibition of ATP-Induced Ca<Superscript>2+</Superscript> Influx by Corticosterone in Dorsal Root Ganglion Neurons

In addition to the classic genomic effects, it is well known that glucocorticoids also have rapid, nongenomic effects on neurons. In the present study, the effect of corticosterone (CORT) on ATP-induced Ca²⁺ mobilization in cultured dorsal root ganglion (DRG) neurons were detected with confocal laser scanning microscopy using fluo-4/AM as a calcium fluorescent indicator that could monitor real-time alterations of intracellular calcium concentration ([Ca²⁺]i). ATP, an algesic agent, caused [Ca²⁺]i increase in DRG neurons by activation of P2X receptor. Pretreatment with CORT (1 nM–1 μM for 5 min) inhibited ATP-induced [Ca²⁺]i increase in DRG neurons. The rapid inhibition of ATP-induced Ca²⁺ response by CORT was concentration-dependent, reversible and could be blocked by glucocorticoid receptor antagonist RU38486 (10 μM). Furthermore, the inhibitory effect of CORT was abolished by protein kinase A inhibitor H89 (10 μM), but was not influenced by protein kinase C inhibitor Chelerythrine chloride (10 μM). On the other hand, membrane-impermeable bovine serum albumin-conjugated corticosterone had no effect on ATP-induced [Ca²⁺]i transients. These observations suggest that a nongenomic pathways may be involved in the effect of CORT on ATP-induced [Ca²⁺]i transients in cultured DRG neurons.     

Calcium Movements in CGRP-treated Cultured Skeletal Muscle Cells: Is There a Role for CGRP in Tension Headaches?

It was previously determined that the site of action of calcitonin gene-related peptide (CGRP) in cardiomyocytes was predominantly at the sarcolemmal calcium release channel, and studies have shown that CGRP has major effects on intracellular cardiomyocyte calcium concentrations. We postulated that CGRP would have similar effects on striated skeletal muscle and determined the effects of CGRP on calcium levels in cultured chick myotubes by fluorescence imaging. Myoblasts were cultured until they were continuous myotubes. Deconvolution fluorescence imaging was employed to visualize subcellular organelles and construct 3D renditions. Myotubes were treated with a high (1 μM) and a low (1 nM) concentration of CGRP for 1 h or 24 h time periods, and real-time fluorescence spectrophotometry with a calcium specific fluoroprobe permitted the acquisition of images and calcium transients. Experiments also used CGRP 8–37 to ensure specificity of action of the full-length neuropeptide. CGRP localizations by image stacking were made using fluorescence deconvolution microscopy and distributions on the myotubes were shown. Myotube contractions and intracellular calcium levels were dose dependent, a high CGRP concentration producing calcium overload. CGRP 8–37 had no effect on contractions or calcium levels. Reconstructed images revealed the neuropeptide to be localized to juxta-nuclear areas, supporting the likelihood of site specific actions. CGRP has dramatic effects on intracellular calcium in striated muscle, high concentrations producing sustained contractions and calcium overload. The results give support to a mechanistic role for CGRP in muscle tension headaches, and underscore the importance in the development of CGRP analogues or receptor antagonists for treatment.     

Effects of Gabapentin on Calcium Transients in Neurons of the Rat Dorsal Root Ganglia

In our experiments on rat dorsal root ganglia (DRG) neurons, we studied the effects of an antiepileptic agent, gabapentin, on calcium transients evoked by depolarization of the membrane using the fluorescence calciumsensitive dye Fura-2/AM. Application of gabapentin to neurons with large-diameter somata practically did not change the characteristics of calcium transients. In mid-sized neurons, the amplitude of transients decreased, on average, by 27% with respect to the control, while in small-sized neurons the transients changed insignificantly (on average, less than by 7%). The mid-sized neurons were additionally subjected to the capsaicin test, which allowed us to differentiate primary nociceptive neurons of this group where TRPV1-type channels are expressed. In capsaicin-sensitive neurons, application of gabapentin led to a decrease in the amplitude of calcium transients, on average, by 37%, while such a decrease was only 16% in capsaicininsensitive neurons. Based on our own data and findings of other researchers on the ability of gabapentin to demonstrate affine binding with the accessory α₂δ subunit of voltage-dependent calcium channels and also on the peculiarities of expression of these channels in somatosensory neurons of the corresponding types, we discuss the probable pattern of expression of subunits of the α₂δ-1 subtype in DRG cells of different sizes. We demonstrated that the effects of gabapentin on calcium transients in nociceptive and hypothetically nonnociceptive mid-sized DRG neurons are selective (the effects in neurons involved in the sensation of acute pain are probably more intense). Neirofiziologiya/Neurophysiology, Vol. 40, No. 4, pp. 281–287, July–August, 2008.     

β-amyloid-induced changes in calcium homeostasis in cultured hippocampal neurons of the rat

A two-wave technique of calciometry with the use of a fluorescence dye, fura-2/AM, was applied for examination of the effect of a protein, β-amyloid (the main component of senile plaques in Alzheimer’s disease), on calcium homeostasis in cultured neurons of the rat hippocampus; β-amyloid was added to the culture medium. In most neurons, the effect of β-amyloid appeared as a more than twofold increase in the basic calcium concentration, as compared with the control (153.4 ± 11.5 and 71.7 ± 5.4 nM, respectively; P < 0.05). The characteristics of calcium transients induced by application of hyperpotassium solution also changed; the amplitude of these transients decreased, and the duration of a part corresponding to calcium release from the cell (rundown of the transient) increased. The mean amplitude of calcium transients under control conditions was 447.5 ± 20.1 nM, while after incubation in the presence of β-amyloid this index dropped to 278.4 ± 22.6 nM. Under control conditions, the decline phase of calcium transients lasted, on average, 100 ± 6 sec, while after incubation of hippocampal cell cultures in the presence of β-amyloid this phase lasted 250 ± 10 sec. Therefore, an excess of β-amyloid influences significantly calcium homeostasis in the nerve cells by disturbing functions of the calcium-controlling systems, such as voltage-operated calcium channels of the plasma membrane and calcium stores of the mitochondria and endoplasmic reticulum. Neirofiziologiya/Neurophysiology, Vol. 40, No. 1, pp. 9–12, January–February, 2008.     

Epileptiform postsynaptic currents in primary culture of rat cortical neurons: Calcium mechanisms

In this study we demonstrate that the primary culture of rat cortical neurons is a convenient model for investigations of epileptogenesis mechanisms and specifically, of the postsynaptic epileptiform currents (EC) reflecting periodical asynchronous glutamate release. In particular, we have revealed that in primary culture of cortical neurons EC can appear spontaneously or can be triggered by the withdrawal of magnesium block of NMDA receptor channels or by shutting down GABAergic inhibition. EC were found to depend on intracellular calcium oscillations. The secondary calcium release from intracellular stores was needed for EC synchronization. EC were suppressed by the influences causing either neuronal calcium overload or decrease of intracellular calcium concentration. Calcium entry into neurons in the case of NMDA receptor hyperactivation or in the case of calcium ionophore ionomycin treatment eliminated EC. The suppression of EC also occurred after a decrease of intracellular calcium concentration induced by BAPTA loaded into the neurons or by stimulation of calcium removal from cells via Na⁺/Ca²⁺ exchanger by 1 nM ouabain. Partial dependence of EC on action potential generation was found. Thus, EC in neurons are activated by intracellular periodic calcium waves within a limited concentration window.     

Impact of Geometrical Characteristics of the Organellar Store and Organelle-Free Cytosol on Intracellular Calcium Dynamics in the Dendrite: a Simulation Study

The dependence of intracellular calcium dynamics on geometrical size relations between calcium-exchanging parts of the intracellular space was studied in mathematical models corresponding to a thin fragment of the Purkinje neuron spiny dendrite. The plasma membrane contained ion channels typical of this cell type, including channels that conduct an excitatory synaptic current, and ion pumps. The model equations took into account calcium exchange between the cytosol, extracellular medium, intracellular store (a cistern of the endoplasmic reticulum, ER), endogenous calcium buffers, and an exogenous buffer (fluorescent dye used in the experiments). The ER membrane contained the calcium pump and channels of calcium-dependent and inositol-3-phosphate-dependent calcium release, as well as leakage channels. With the compartment size fixed, the ER cistern diameter was varied so that the proportion of the organelle in the total volume changed from 1 to 36%. Under these conditions, identical synaptic excitation caused similar electrical reactions (calcium spikes) but different concentration responses. Equal increments in the ER diameter led to unequal, more pronounced at thicker diameters, increments of the peak cytosolic concentrations of Са²⁺ ([Ca²⁺] _i ) and of a Са²⁺-fluorescent dye complex [CaD], as well as those of the Са²⁺ concentration in the dendrite ER (characterized by a shift from the basal level, Δ[Ca²⁺]_ER). The changes in [Ca²⁺] _i and [CaD] followed more adequately those in the volume of the organelle-free cytosol, while Δ[Ca²⁺]_ER changes were more similar to those in the ER membrane area. Therefore, the relative occupancy of the intracellular volume by organellar calcium stores and their sizes in a dendritic compartment are important structural factors that essentially modulate the calcium dynamics, and this structural dependence can be adequately reflected in the experiments using fluorophores. Neirofiziologiya/Neurophysiology, Vol. 41, No. 1, pp. 19–31, January–February, 2009.     

Calcium Signaling in <Emphasis Type="Italic">Carassius</Emphasis> Cerebellar Neurons: Role of the Mitochondria

We studied the involvement of the mitochondria playing the role of a calcium store in the control of calcium exchange in cerebellar neurons of a fish species tolerant to hypoxia, crucian (Carassius gibelio). In our experiments we used an ionophore, CCCP, that blocked accumulation of calcium by the above organelles. The intracellular concentration of free Ca²⁺ ([Ca²⁺] _і ) was measured using a calcium-sensitive dye, Fura-2AM, and the microfluorescent technique. We found that cerebellar neurons of Carassius gibelio possess a well-expressed system clearing the cytoplasm from excessive Ca²⁺, and the mitochondria are actively involved in this process. Under conditions of suppression of the process of accumulation of calcium by the mitochondria under the action of CCCP, the amplitude of calcium transients increased by about 50%. In addition, the decay phase of depolarization-induced intracellular calcium transients was slowed down considerably. Therefore, our experiments are indicative of the significant role of the mitochondria in the control of calcium dynamics in cerebellar neurons of Carassius gibelio in the course of functional activity of these cells.     

Potassium permeability of voltage-operated calcium channels of dorsal root ganglion neurons in a calcium-free medium

In freshly isolated neurons of the rat spinal ganglia, we studied the behavior of voltage-operated calcium channels of these cells under conditions of the absence of calcium ions in the extracellular solution; a patch-clamp technique in the whole-cell configuration was used. We found that such channels in a part of the studied neurons lose their selectivity in a calcium-free potassium-containing solution and become capable of passing an inward potassium current. This current was inhibited by blockers of voltage-operated calcium channels, nifedipine and nickel, and also was to some extent inhibited by caffeine. The latter effect is realized, perhaps, due to calcium-dependent inactivation of calcium channels induced by the action of calcium ions released from the endoplasmic reticulum upon caffeine-induced activation of ryanodine receptors. The peculiarities of current-voltage relationships and characteristics of activation/inactivation of calcium channels modified in calcium-free medium and the possible mechanisms of such modification are discussed. Neirofiziologiya/Neurophysiology, Vol. 40, No. 2, pp. 93–99, March–April, 2008.     

Control of spontaneous synchronous Ca<Superscript>2+</Superscript> oscillations in hippocampal neurons by GABAergic neurons containing kainate receptors without desensitization

Previously we have shown that in culture of rat hippocampal neurons, the calcium responses of individual cells (changes of cytoplasmic free Ca²⁺ concentration in response to agonists of glutamate kainate receptors) differed in shape and amplitude (Kononov A.V., Bal’ N.V., Zinchenko V.P. 2011. Biochemistry (Moscow) Suppl. Series A: Membrane and Cell Biology. 5 (2), 162–170). In the majority of neurons, the amplitudes of calcium response were regularly distributed, although there were a small number of cells that generated the desensitization-free signals of far greater amplitudes. In these cells, the desensitization inhibitors did not increase the amplitude of calcium response. We identified these neurons and revealed their function. The agonists of kainate receptors inhibited the synchronized spontaneous Ca²⁺ oscillations, decreased the baseline calcium level in the majority of neurons, and considerably elevated it in some of them. After washout of the agonists, the oscillations were restored in all neurons only after a certain time lag determined by the period needed for calcium concentration to decrease to subbasal level in specific neurons with high calcium signal amplitude. This observation indicates the command role of these neurons in synchronizing the activity of the entire population. To identify the subtype of KA receptors in these neurons, we used especially selective agonists and showed that KA receptors of the neurons characterized with desensitization-free calcium signals of unusually great amplitude contained GluR5/GLUK1 subunits. These receptors are known to be located mostly in the presynaptic membrane, where they promote exocytosis of neurotransmitters due to elevation of the Ca²⁺ conductivity. Having marked the positions of these neurons, we fixed the preparation and stained the cells with fluorescently labeled antibodies raised against glutamate decarboxylase, an enzyme which is selectively expressed in GABAergic neurons. The experiments demonstrated that antibodies were localized only in the neurons, where the kainate receptor agonist evoked desensitization-free calcium responses of especially large amplitude. Thus, GABAergic neurons control the synchronous activity of a large number of neurons via glutamate-evoked activation of specific presynaptic kainate receptors with GluR5/GLUK1 subunits leading to desensitization-free calcium signals of especially large amplitude.     

Voltage-dependent calcium channels in cultivated neurons of the rat hippocampus

Calcium currents through the somatic membrane of cultivated (a low-density culture) hippocampal neurons of rats were studied with the use of a patch-clamp technique in the whole-cell configuration. Low- and high-threshold components of calcium currents were found in the somata of all studied cells. Low-threshold currents were activated at a membrane potential of about−75 mV and reached the maximum amplitude at −45±4 mV, while the maximum amplitude of high-threshold currents was observed at 17±6 mV. Low-threshold calcium currents differed from high-threshold current in weak suppression by low Cd²⁺ concentration (10–20 μM), while Ni²⁺ inhibited both types of calcium currents to an equal extent. Experiments with organic channel blockers showed that in most neurons at least four channel types were expressed: these were L, N, P, and channels insensitive to the used blockers (presumably, R-type). A blocker of L-type calcium channels, nifedipine (10 μM), blocked, on the average, 22.7±5.2%; a blocker of N-type channels, ω-CTx-GVIA (1.0 μM), blocked 30.0±5.0% and a blocker of P/Q channels, ω-Aga-IVA (200 nM), blocked 37.2±13.3% of the integral high-threshold current. A resistive component equalled 15.7±5.1% of the latter current. It is concluded that hippocampal neurons cultivated with a low density express a pharmacologically heterogeneous population of calcium channels, and the relative proportions of different type channels are close to the earlier described channel type composition in rat hippocampal slices. Our study shows that the low-density culture can be used as an adequate model for studying calcium channels in the somatic membrane of hippocampal neurons.     

Electrically induced changes in Ca2+ in Helisoma neurons: Regional and neuron-specific differences and implications for neurite outgrowth

The present experiments addressed the questions of how electrical stimulation influenced the magnitude, time course, and regional levels of free intracellular calcium of different identified neurons. The calcium concentration in the growth cones, neurites and cell bodies of Helisoma buccal neurons B4 and B19 was measured while somata were electrically stimulated via an intracellular electrode. The findings showed that calcium levels in B4 and B19 increased monotonically with increasing stimulation frequency. However, the range of calcium levels evoked by electrical stimulation differed significantly for each type of neuron. The greater increase in calcium concentration in B4 was correlated with its longer duration action potential compared to B19. The increase in calcium concentration was much smaller in the cell bodies than in the growth cones and neurites. Extending the duration of the B19 action potential produced a sixfold increase in the change in calcium concentration at 2 Hz stimulation. Under conditions where the electrical stimulation produced a calcium concentration of < 160 nM, the elevated level of free intracellular calcium remained constant. When calcium concentration increased above 200 nM in both identified neurons, an initial peak concentration was followed by a decline to a lower concentration suggesting increased calcium buffering occurring above 200 nM. By correlating the calcium concentration data herein with growth data from a previous study, we suggest that specific calcium levels that influence neurite outgrowth may differ widely between neurons. © 1997 John Wiley & Sons, Inc. J Neurobiol 32: 150–162, 1997.     

An involvement of BDNF and PI3-K/Akt in the anti-apoptotic effect of memantine on staurosporine-evoked cell death in primary cortical neurons

Memantine, a clinically used NMDA receptor antagonist possesses neuroprotective properties, but the exact mechanisms of its beneficial action on neuronal survival are poorly recognized. In the present study, some intracellular mechanisms of memantine effects on staurosporine-evoked cell death were investigated in primary cortical neurons. Memantine (0.1–2 μM) suppressed neuronal apoptosis evoked by staurosporine in 7 DIV cortical neurons, whereas other antagonists of NMDA receptor, MK-801 (1 μM) and AP-5 (100 μM) were ineffective. The anti-apoptotic effects of memantine were not connected with any changes in cytoplasmic calcium concentration or reactive oxygen species level. The immunoblot analysis showed that the staurosporine induced a decrease in p-Akt protein kinase level and that this effect was reversed by memantine treatment. Moreover, the PI3-K inhibitors, wortmannin and LY 294002 attenuated the anti-apoptotic action of memantine on staurosporine-induced cell damage. Furthermore, the ELISA studies showed increased cellular and released BDNF protein level after combined treatment with memantine and staurosporine. There was no effect of memantine on the activation and expression of other protein kinases involved in the mechanism of cellular survival, i.e. ERK1/2, JNK and GSK3-β. The obtained data suggest an NMDAR-independent action of memantine in attenuation of neuronal apoptosis and point to the engagement of BDNF and PI3-K/Akt pathway in these processes.     

Key role of calcium signaling in synaptic transmission

The review analyzes current concepts on the role of calcium signals in the process of synaptic neuron-to-neuron and neuron-effector transmission and on the respective intracellular mechanisms (participation of different types of ion channels, mitochondria, and endoplasmic reticulum). The involvement of calcium both in the transmission per se, in particular in the process of exocytotic neurotransmitter release, and in long-lasting modulations of the efficacy of synaptic transmission (potentiation or depression) is considered. Neirofiziologiya/Neurophysiology, Vol. 39, Nos. 4/5, pp. 290–293, July–October, 2007.     

Dynamics of two electrically coupled chaotic neurons: Experimental observations and model analysis

Conductance-based models of neurons from the lobster stomatogastric ganglion (STG) have been developed to understand the observed chaotic behavior of individual STG neurons. These models identify an additional slow dynamical process – calcium exchange and storage in the endoplasmic reticulum – as a biologically plausible source for the observed chaos in the oscillations of these cells. In this paper we test these ideas further by exploring the dynamical behavior when two model neurons are coupled by electrical or gap junction connections. We compare in detail the model results to the laboratory measurements of electrically-coupled neurons that we reported earlier. The experiments on the biological neurons varied the strength of the effective coupling by applying a parallel, artificial synapse, which changed both the magnitude and polarity of the conductance between the neurons. We observed a sequence of bifurcations that took the neurons from strongly synchronized in-phase behavior, through uncorrelated chaotic oscillations to strongly synchronized – and now regular – out-of-phase behavior. The model calculations reproduce these observations quantitatively, indicating that slow subcellular processes could account for the mechanisms involved in the synchronization and regularization of the otherwise individual chaotic activities. Received: 28 June 1999 / Accepted in revised form: 30 June 2000