Astrocyte-induced modulation of synaptic transmission

1999 ◽  
Vol 77 (9) ◽  
pp. 699-706 ◽  
Author(s):  
Alfonso Araque ◽  
Rita P Sanzgiri ◽  
Vladimir Parpura ◽  
Philip G Haydon
Keyword(s):  
Synaptic Transmission ◽  
Glutamate Receptors ◽  
Neuronal Activity ◽  
Hippocampal Neurons ◽  
Calcium Waves ◽  
Metabotropic Glutamate ◽  
Intracellular Ca ◽  
Inward Currents ◽  
Neuronal Electrical Activity ◽  
Cultured Hippocampal Neurons

The idea that astrocytes simply provide structural and trophic support to neurons has been challenged by recent evidence demonstrating that astrocytes exhibit a form of excitability and communication based on intracellular Ca2+ variations and intercellular Ca2+ waves, which can be initiated by neuronal activity. These astrocyte Ca2+ variations have now been shown to induce glutamate-dependent Ca2+ elevations and slow inward currents in neurons. More recently, it has been demonstrated that synaptic transmission between cultured hippocampal neurons can be directly modulated by astrocytes. We have reported that astrocyte stimulation can increase the frequency of miniature synaptic currents. Furthermore, we also have demonstrated that an elevation in the intracellular Ca2+ in astrocytes induces a reduction in both excitatory and inhibitory evoked synaptic transmission through the activation of selective presynaptic metabotropic glutamate receptors.Key words: astrocyte-neuron signaling, glutamate receptors, calcium waves, neuronal electrical activity, synaptic transmission.

Persistent current oscillations produced by activation of metabotropic glutamate receptors in immature rat CA3 hippocampal neurons

1995 ◽  
Vol 73 (4) ◽  
pp. 1422-1429 ◽  
Author(s):  
L. Aniksztejn ◽  
M. Sciancalepore ◽  
Y. Ben Ari ◽  
E. Cherubini
Keyword(s):  
Glutamate Receptors ◽  
Hippocampal Neurons ◽  
Metabotropic Glutamate Receptors ◽  
Calcium Release ◽  
Release Process ◽  
Metabotropic Glutamate ◽  
Voltage Dependent ◽  
Inward Currents ◽  
Presynaptic Nerve Terminals ◽  
Calcium Induced Calcium Release

1. The single-electrode voltage-clamp technique was used to study the effects of the metabotropic glutamate receptors (mGluRs) agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD, ACPD, 3-10 microM) on CA3 hippocampal neurons during the 1st 10 days of postnatal (P) life and in adulthood. 2. Repeated applications of 1S,3R-ACPD, in the presence of tetrodotoxin (TTX, 1 microM), tetraethylammonium chloride (TEACl 10 mM), and CsCl (2 mM), induced in immature but not in adult neurons periodic inward currents (PICs) that persisted for several hours after the last application of the agonist. 3. PICs, which were generated by nonspecific cationic currents, reversed polarity at 2.8 +/- 3 (SD) mV. They were reversibly blocked by kynurenic acid (1 mM), suggesting that they were mediated by glutamate acting on ionotropic receptors. They were also abolished in a nominally Ca(2+)-free medium. 4. PICs were irreversibly abolished by thapsigargin (10 microM) but were unaffected by ryanodine (10-40 microM). Caffeine (2 mM) also reversibly blocked PICs; this effect was independent from adenosine 3',5'-cyclic monophosphate (cAMP) accumulation, inhibition of voltage-dependent Ca2+ current, or blockade of adenosine receptors. 5. We suggest that, in neonatal slices, mGluRs-induced PICs are triggered by elevation of [Ca2+]i, after mobilization of Ca2+ from inositol 1,4,5-trisphosphate (InsP3)-sensitive stores. This will lead to a persistent, pulsatile release of glutamate from presynaptic nerve terminals, a phenomenon that is probably maintained via a calcium-induced-calcium release process.

Heterologous modulation of inhibitory synaptic transmission by metabotropic glutamate receptors in cultured hippocampal neurons

1996 ◽  
Vol 75 (2) ◽  
pp. 885-893 ◽  
Author(s):  
R. M. Fitzsimonds ◽  
M. A. Dichter
Keyword(s):  
Synaptic Transmission ◽  
Glutamate Receptors ◽  
Hippocampal Neurons ◽  
Metabotropic Glutamate Receptors ◽  
Glutamate Uptake ◽  
Low Density ◽  
Inhibitory Synaptic Transmission ◽  
Metabotropic Glutamate ◽  
Mglur Antagonist ◽  
Uptake Mechanisms

1. Whole cell patch-clamp recordings of monosynaptically connected pairs of hippocampal neurons in very low-density culture were performed to determine the effects of the activation of metabotropic glutamate receptors (mGluRs) on inhibitory terminals. The mGluR agonist (1S, 3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S, 3R)-ACPD] and the recently described mGluR antagonist (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG) were used. In addition, the glutamate uptake inhibitors L-trans-pyrrolidine-2,4-dicarboxylate (L-trans-PDC) and D,L-beta-threo-hydroxyaspartate (THA) were used to determine whether endogenous agents (presumably glutamate) could activate mGluRs at inhibitory terminals. Previous reports of the role of mGluRs on inhibitory terminals were performed in slice preparations; our use of patch-clamp recordings from isolated pairs of hippocampal neurons is uniquely useful for the study of inhibitory synaptic transmission in the absence of polysynaptic connectivity. 2. The mGluR agonist (1S, 3R)-ACPD (100 microM) reversibly decreased the amplitude of evoked inhibitory postsynaptic currents (IPSCs) in all pairs tested; this effect was completely blocked by coapplication of the mGluR antagonist MCPG (500 microM) with (1S, 3R)-ACPD. MCPG (500 microM) alone had no effect on IPSC amplitude. These results indicate that all inhibitory neurons in our cultures express functional mGluRs in their terminals. 3. Examination of the frequency and the distribution of amplitudes of miniature IPSCs (mIPSCs) provide indications of changes in the sensitivity of postsynaptic receptors and/or of changes in the process of presynaptic transmitter release. Recordings of miniature currents from hippocampal neurons cultured at very low density makes possible the analysis of mIPSCs that arise from a single input, whereas in high density or slice preparations, spontaneous miniature currents reflect numerous synaptic inputs. No change in the amplitudes or frequency of the mIPSCs were observed upon application of (1S, 3R)-ACPD (100 microM). Thus we conclude that the depression of the evoked IPSC amplitude by (1S, 3R)-ACPD is mediated by a presynaptic mechanism in these isolated pairs of hippocampal neurons. 4. The glutamate uptake inhibitor L-trans-PDC also reduced IPSC amplitude in 8 of 13 pairs. In these eight pairs, an increase in N-methyl-D-aspartate (NMDA) receptor-mediated membrane noise indicated an increase in ambient concentrations of glutamate induced by L-trans-PDC. In the remaining five pairs, membrane noise remained unaffected by L-trans-PDC, and IPSCs were not attenuated. Similar results were observed with the use of the uptake inhibitor THA. The mGluR antagonist MCPG blocked the effects of L-trans-PDC and THA on IPSC amplitude. We propose that inhibition of glutamate uptake mechanisms results in activation of mGluRs on GABAergic terminals via endogenous sources of glutamate and that the uptake inhibitors (L-trans-PDC and THA) do not directly activate the metabotropic receptor. 5. Presynaptic receptors and active modulation of uptake mechanisms are clearly involved in a wide range of physiological and pathological synaptic events. The data presented here suggest that heterosynaptic modulation of inhibitory synaptic transmission by metabotropic glutamate receptors may be important for the maintenance and plasticity of the balances between excitatory and inhibitory synaptic transmission in the CNS.

scholarly journals Activity-dependent BDNF release via endocytic pathways is regulated by synaptotagmin-6 and complexin

2015 ◽  
Vol 112 (32) ◽  
pp. E4475-E4484 ◽  
Author(s):  
Yu-Hui Wong ◽  
Chia-Ming Lee ◽  
Wenjun Xie ◽  
Bianxiao Cui ◽  
Mu-ming Poo
Keyword(s):  
Quantum Dots ◽  
Glutamate Receptors ◽  
Neuronal Activity ◽  
Hippocampal Neurons ◽  
Molecular Mechanisms ◽  
Dependent Manner ◽  
Synaptic Modulation ◽  
Activity Dependent ◽  
Endocytic Pathways ◽  
Cultured Hippocampal Neurons

Brain-derived neurotrophic factor (BDNF) is known to modulate synapse development and plasticity, but the source of synaptic BDNF and molecular mechanisms regulating BDNF release remain unclear. Using exogenous BDNF tagged with quantum dots (BDNF-QDs), we found that endocytosed BDNF-QDs were preferentially localized to postsynaptic sites in the dendrite of cultured hippocampal neurons. Repetitive neuronal spiking induced the release of BDNF-QDs at these sites, and this process required activation of glutamate receptors. Down-regulating complexin 1/2 (Cpx1/2) expression eliminated activity-induced BDNF-QD secretion, although the overall activity-independent secretion was elevated. Among eight synaptotagmin (Syt) isoforms examined, down-regulation of only Syt6 impaired activity-induced BDNF-QD secretion. In contrast, activity-induced release of endogenously synthesized BDNF did not depend on Syt6. Thus, neuronal activity could trigger the release of endosomal BDNF from postsynaptic dendrites in a Cpx- and Syt6-dependent manner, and endosomes containing BDNF may serve as a source of BDNF for activity-dependent synaptic modulation.

Frequency-dependent depression of excitatory synaptic transmission is independent of activation of MCPG-sensitive presynaptic metabotropic glutamate receptors in cultured hippocampal neurons

1995 ◽  
Vol 74 (4) ◽  
pp. 1671-1674 ◽  
Author(s):  
R. Maki ◽  
D. D. Cummings ◽  
M. A. Dichter
Keyword(s):  
Glutamate Receptors ◽  
High Frequency ◽  
Hippocampal Neurons ◽  
Metabotropic Glutamate Receptors ◽  
Frequency Dependent ◽  
Paired Pulse ◽  
Metabotropic Glutamate ◽  
Whole Cell Patch Clamp ◽  
Mglur Antagonist ◽  
Cultured Hippocampal Neurons

1. A paired-pulse paradigm, and a high-frequency train followed by a test pulse, were used to investigate the possible role of presynaptic metabotropic glutamate receptors (mGluRs) in frequency-dependent modulation of the amplitude of excitatory post-synaptic currents (EPSCs). Paired whole cell patch-clamp recordings from monosynaptically connected hippocampal neurons maintained in very low-density cultures were performed, using the mGluR antagonist (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG, 500 microM) and the mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD, 100 microM]. 2. Paired-pulse depression (PPD) was observed in all the excitatory pairs recorded. The average PPD ratio (amplitude of the 2nd EPSC divided by the amplitude of the 1st EPSC) was 0.80 +/- 0.1 (SD) (n = 8). Application of the mGluR antagonist MCPG had no effect on the amplitude of the EPSCs and did not affect the ratio of the two EPSCs (PPD ratio 0.79 +/- 0.2). 3. The amplitudes of 10 successive EPSCs stimulated at a high frequency (20 Hz) decremented on average in both 4 mM extracellular Ca2+ (n = 5) and in 1 mM extracellular Ca2+ (n = 6). In all pairs tested, posttetanic depression (PTD) was observed (PTD ratio 0.7 +/- 0.2). Bath application of MCPG (500 microM) did not affect the amplitudes of the EPSCs during the train; MCPG also did not affect PTD. 4. The mGluR agonist (1S,3R)-ACPD depressed the amplitudes of the EPSCs in both the paired-pulse (1st EPSC, 35 +/- 9%; 2nd EPSC, 36 +/- 10%) and posttetanic pulse (1 and 4 mM extracellular Ca2+) paradigms. The amount of depression observed, both PPD and PTD, remained unaffected by application of (1S,3R)-ACPD. Coapplication of the antagonist MCPG (500 microM) blocked the effects of (1S,3R)-ACPD (100 microM). 5. We conclude that frequency-dependent depression of EPSC amplitudes occurs independent of endogenous activation of MCPG-sensitive mGluRs in cultured hippocampal neurons. Moreover, we demonstrate that exogenous activation of mGluRs by the agonist (1S,3R)-ACPD can produce additional EPSC depression above that already present due to frequency-dependent mechanisms.

Effect of Lamotrigine on the Ca2+-Sensing Cation Current in Cultured Hippocampal Neurons

2001 ◽  
Vol 86 (5) ◽  
pp. 2520-2526 ◽  
Author(s):  
Zhi-Gang Xiong ◽  
Xiang-Ping Chu ◽  
J. F. MacDonald
Keyword(s):  
Action Potentials ◽  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Membrane Depolarization ◽  
Slow Inward Current ◽  
Calcium Sensing ◽  
Cation Current ◽  
Imaging Experiment ◽  
Intracellular Ca ◽  
Cultured Hippocampal Neurons

Concentrations of extracellular calcium ([Ca2+]e) in the CNS decrease substantially during seizure activity. We have demonstrated previously that decreases in [Ca2+]e activate a novel calcium-sensing nonselective cation (csNSC) channel in hippocampal neurons. Activation of csNSC channels is responsible for a sustained membrane depolarization and increased neuronal excitability. Our study has suggested that the csNSC channel is likely involved in generating and maintaining seizure activities. In the present study, the effects of anti-epileptic agent lamotrigine (LTG) on csNSC channels were studied in cultured mouse hippocampal neurons using patch-clamp techniques. At a holding potential of −60 mV, a slow inward current through csNSC channels was activated by a step reduction of [Ca2+]e from 1.5 to 0.2 mM. LTG decreased the amplitude of csNSC currents dose dependently with an IC50 of 171 ± 25.8 (SE) μM. The effect of LTG was independent of membrane potential. In the presence of 300 μM LTG, the amplitude of csNSC current was decreased by 31 ± 3% at −60 mV and 29 ± 2.9% at +40 mV ( P > 0.05). LTG depressed csNSC current without affecting the potency of Ca2+ block of the current (IC50 for Ca2+block of csNSC currents in the absence of LTG: 145 ± 18 μM; in the presence of 300 μM LTG: 136 ± 10 μM. n = 5, P > 0.05). In current-clamp recordings, activation of csNSC channel by reducing the [Ca2+]e caused a sustained membrane depolarization and an increase in the frequency of spontaneous firing of action potentials. LTG (300 μM) significantly inhibited csNSC channel-mediated membrane depolarization and the excitation of neurons. Fura-2 ratiometric Ca2+imaging experiment showed that LTG also inhibited the increase in intracellular Ca2+ concentration induced by csNSC channel activation. The effect of LTG on csNSC channels may partially contribute to its broad spectrum of anti-epileptic actions.

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