Group I mGluR Activation Turns on a Voltage-Gated Inward Current in Hippocampal Pyramidal Cells

2000 ◽  
Vol 83 (5) ◽  
pp. 2844-2853 ◽  
Author(s):  
Shih-Chieh Chuang ◽  
Riccardo Bianchi ◽  
Robert K. S. Wong
Keyword(s):  
Metabotropic Glutamate Receptor ◽  
Hippocampal Slices ◽  
Pyramidal Cells ◽  
Calcium Currents ◽  
Resting Potential ◽  
Inward Current ◽  
Voltage Gated ◽  
Group I ◽  
Ionic Mechanisms ◽  
Ca3 Pyramidal Cells

A unique property of the group I metabotropic glutamate receptor (mGluR)-induced depolarization in hippocampal cells is that the amplitude of the depolarization is larger when the response is elicited at more depolarized membrane potentials. Our understanding of the conductance mechanism underlying this voltage-dependent response is incomplete. Through the use of current-clamp and single-electrode voltage-clamp recordings in guinea pig hippocampal slices, we examined the group I mGluR-induced depolarization in CA3 pyramidal cells. The group I mGluR agonists ( S)-3-hydroxyphenylglycine and ( S)-3,5-dihydroxyphenylglycine turned on a voltage-gated inward current ( I mGluR(V)), which was pharmacologically distinct from the voltage-gated sodium and calcium currents intrinsic to the cells. I mGluR(V)was a slowly activating, noninactivating current with a threshold at about −75 mV. In addition to the activation of I mGluR(V), group I mGluR stimulation also produced a voltage-independent decrease in the K+conductance. Our results suggest that the depolarization induced by group I mGluR activation is generated by two ionic mechanisms—a heretofore unrecognized voltage-gated inward current ( I mGluR(V)) that is turned on by depolarization and a voltage-insensitive inward current that results from a turn-off of the K+ conductance. The low-threshold and noninactivating properties of I mGluR(V)allow the current to play a significant role in setting the resting potential and firing pattern of CA3 pyramidal cells.

Group I mGluR Activation Causes Voltage-Dependent and -Independent Ca2+ Rises in Hippocampal Pyramidal Cells

1999 ◽  
Vol 81 (6) ◽  
pp. 2903-2913 ◽  
Author(s):  
Riccardo Bianchi ◽  
Steven R. Young ◽  
Robert K. S. Wong
Keyword(s):  
Metabotropic Glutamate Receptor ◽  
Hippocampal Slices ◽  
Pyramidal Cells ◽  
Membrane Depolarization ◽  
Membrane Hyperpolarization ◽  
Voltage Gated ◽  
Group I ◽  
Voltage Dependent ◽  
Intracellular Ca ◽  
Hippocampal Pyramidal Cells

Group I mGluR activation causes voltage-dependent and -independent Ca2+ rises in hippocampal pyramidal cells. Application of the metabotropic glutamate receptor (mGluR) agonist (1 S,3 R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) or the selective group I mGluR agonist ( S)-3,5-dihydroxyphenylglycine (DHPG) depolarized both CA3 and CA1 pyramidal cells in guinea pig hippocampal slices. Simultaneous recordings of voltage and intracellular Ca2+ levels revealed that the depolarization was accompanied by a biphasic elevation of intracellular Ca2+ concentration ([Ca2+]i): a transient calcium rise followed by a delayed, sustained elevation. The transient [Ca2+]i rise was independent of the membrane potential and was blocked when caffeine was added to the perfusing solution. The sustained [Ca2+]i rise appeared when membrane depolarization reached threshold for voltage-gated Ca2+ influx and was suppressed by membrane hyperpolarization. The depolarization was associated with an increased input resistance and persisted when either the transient or sustained [Ca2+]i responses was blocked. mGluR-mediated voltage and [Ca2+]i responses were blocked by (+)-α-methyl-4-carboxyphenylglycine (MCPG) or ( S)-4-carboxy-3-hydroxyphenylglycine (4C3HPG). These data suggest that in both CA3 and CA1 hippocampal cells, activation of group I mGluRs produced a biphasic accumulation of [Ca2+]i via two paths: a transient release from intracellular stores, and subsequently, by influx through voltage-gated Ca2+ channels. The concurrent mGluR-induced membrane depolarization was not caused by the [Ca2+]i rise.

Modulation of Multiple Potassium Currents by Metabotropic Glutamate Receptors in Neurons of the Hypothalamic Supraoptic Nucleus

1997 ◽  
Vol 78 (6) ◽  
pp. 3428-3437 ◽  
Author(s):  
L. A. Schrader ◽  
J. G. Tasker
Keyword(s):  
Glutamate Receptors ◽  
Supraoptic Nucleus ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Outward Current ◽  
Magnocellular Neurons ◽  
Inward Current ◽  
Voltage Gated ◽  
Metabotropic Glutamate ◽  
Group I

Schrader, L. A. and J. G. Tasker. Modulation of multiple potassium currents by metabotropic glutamate receptors in neurons of the hypothalamic supraoptic nucleus. J. Neurophysiol. 78: 3428–3437, 1997. We studied the effects of activation of the metabotropic glutamate receptors on intrinsic currents of magnocellular neurons of the supraoptic nucleus (SON) with whole cell patch-clamp and conventional intracellular recordings in coronal slices (400 μm) of the rat hypothalamus. Trans-(±)-1-amino-1,3-cyclopentane dicarboxylic acid ( trans-ACPD, 10–100 μM), a broad-spectrum metabotropic glutamate receptor agonist, evoked an inward current (18.7 ± 3.45 pA) or a slow depolarization (7.35 ± 4.73 mV) and a 10–30% decrease in whole cell conductance in ∼50% of the magnocellular neurons recorded at resting membrane potential. The decrease in conductance and the inward current were caused largely by the attenuation of a resting potassium conductance because they were reduced by the replacement of intracellular potassium with an equimolar concentration of cesium or by the addition of potassium channel blockers to the extracellular medium. In some cells, trans-ACPD still elicited a small inward current after blockade of potassium currents, which was abolished by the calcium channel blocker, CdCl2. Trans-ACPD also reduced voltage-gated and Ca2+-activated K+ currents in these cells. Trans-ACPD reduced the transient outward current ( I A) by 20–70% and/or the I A-mediated delay to spike generation in ∼60% of magnocellular neurons tested. The cells that showed a reduction of I A generally also showed a 20–60% reduction in a voltage-gated, sustained outward current. Finally, trans-ACPD attenuated the Ca2+-dependent outward current responsible for the afterhyperpolarization ( I AHP) in ∼60% of cells tested. This often revealed an underlying inward current thought to be responsible for the depolarizing afterpotential seen in some magnocellular neurons. (RS)-3,5-dihydroxyphenylglycine, a group I receptor-selective agonist, mimicked the effects of trans-ACPD on the resting and voltage-gated K+ currents. (RS)-α-methyl-4-carboxyphenylglycine, a group I/II metabotropic glutamate receptor antagonist, blocked these effects. A group II receptor agonist, 2S,1′S,2′S-2carboxycyclopropylglycine and a group III receptor agonist, l(+)-2-amino-4-phosphonobutyric acid, had no effect on the resting or voltage-gated K+ currents, indicating that the reduction of K+ currents was mediated by group I receptors. About 80% of the SON cells that were labeled immunohistochemically for vasopressin responded to metabotropic glutamate receptor activation, whereas only 33% of labeled oxytocin cells responded, suggesting that metabotropic receptors are expressed preferentially in vasopressinergic neurons. These data indicate that activation of the group I metabotropic glutamate receptors leads to an increase in the postsynaptic excitability of magnocellular neurons by blocking resting K+ currents as well as by reducing voltage-gated and Ca2+-activated K+ currents.

Requirement of Protein Synthesis for Group I mGluR-Mediated Induction of Epileptiform Discharges

1998 ◽  
Vol 80 (2) ◽  
pp. 989-993 ◽  
Author(s):  
Lisa R. Merlin ◽  
Peter J. Bergold ◽  
Robert K. S. Wong
Keyword(s):  
Protein Synthesis ◽  
Metabotropic Glutamate Receptor ◽  
Hippocampal Slices ◽  
Pyramidal Cells ◽  
Progressive Increase ◽  
Protein Synthesis Inhibitors ◽  
Burst Frequency ◽  
Metabotropic Glutamate ◽  
Epileptiform Discharges ◽  
Group I

Merlin, Lisa R., Peter J. Bergold, and Robert K. S. Wong. Requirement of protein synthesis for group I mGluR-mediated induction of epileptiform discharges. J. Neurophysiol. 80: 989–993, 1998. Picrotoxin (50 μM) elicited rhythmic synchronized bursting in CA3 pyramidal cells in guinea pig hippocampal slices. Addition of the selective group I metabotropic glutamate receptor (mGluR) agonist ( S)-3,5-dihydroxyphenylglycine (25 μM) elicited an increase in burst frequency. This was soon followed by a slowly progressive increase in burst duration (BD), converting the brief 250–520 ms picrotoxin-induced synchronized bursts into prolonged discharges of 1–5 s in duration. BD was significantly increased within 60 min and reached a maximum after 2–2.5 h of agonist exposure. The protein synthesis inhibitors anisomycin (15 μM) or cycloheximide (25 μM) significantly impeded the mGluR-mediated development of the prolonged bursts; 90–120 min of agonist application failed to elicit the expected burst prolongation. By contrast, the mGluR-mediated enhancement of burst frequency progressed unimpeded. Furthermore, protein synthesis inhibitors had no significant effect on the frequency or duration of fully developed mGluR-induced prolonged discharges. These results suggest that the group I mGluR-mediated prolongation of synchronized bursts has a protein synthesis-dependent mechanism.

Calcium- and Calmodulin-Dependent Inactivation of Calcium Channels in Inner Hair Cells of the Rat Cochlea

2008 ◽  
Vol 99 (5) ◽  
pp. 2183-2193 ◽  
Author(s):  
Lisa Grant ◽  
Paul Fuchs
Keyword(s):  
Calcium Channels ◽  
Hair Cells ◽  
Calcium Currents ◽  
Resting Potential ◽  
Resting Membrane Potential ◽  
Inner Hair Cells ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Dependent Inactivation ◽  
Calcium Buffering

Modulation of voltage-gated calcium channels was studied in inner hair cells (IHCs) in an ex vivo preparation of the apical turn of the rat organ of Corti. Whole cell voltage clamp in the presence of potassium channel blockers showed inward calcium currents with millisecond activation and deactivation kinetics. When temperature was raised from 22 to 37°C, the calcium currents of immature IHCs [<12 days postnatal (P12)] increased threefold in amplitude, and developed more pronounced inactivation. This was determined to be calcium-dependent inactivation (CDI) on the basis of its reliance on external calcium (substitution with barium), sensitivity to internal calcium-buffering, and voltage dependence (reflecting the calcium driving force). After the onset of hearing at P12, IHC calcium current amplitude and the extent of inactivation were greatly reduced. Although smaller than in prehearing IHCs, CDI remained significant in the mature IHC near the resting membrane potential. CDI in mature IHCs was enhanced by application of the endoplasmic calcium pump blocker, benzo-hydroquinone. Conversely, CDI in immature IHCs was reduced by calmodulin inhibitors. Thus voltage-gated calcium channels in mammalian IHCs are subject to a calmodulin-mediated process of CDI. The extent of CDI depends on the balance of calcium buffering mechanisms and may be regulated by calmodulin-specific processes. CDI provides a means for the rate of spontaneous transmitter release to be adjusted to variations in hair cell resting potential and steady state calcium influx.

Group I mGluRs Increase Excitability of Hippocampal CA1 Pyramidal Neurons by a PLC-Independent Mechanism

2002 ◽  
Vol 88 (1) ◽  
pp. 107-116 ◽  
Author(s):  
David R. Ireland ◽  
Wickliffe C. Abraham
Keyword(s):  
Metabotropic Glutamate Receptors ◽  
Pyramidal Neurons ◽  
Hippocampal Slices ◽  
Pyramidal Cells ◽  
Receptor Subtypes ◽  
Ca1 Pyramidal Neurons ◽  
Group I ◽  
Hippocampal Ca1 ◽  
Group I Mglurs ◽  
Induced Changes

Previous studies have implicated phospholipase C (PLC)-linked Group I metabotropic glutamate receptors (mGluRs) in regulating the excitability of hippocampal CA1 pyramidal neurons. We used intracellular recordings from rat hippocampal slices and specific antagonists to examine in more detail the mGluR receptor subtypes and signal transduction mechanisms underlying this effect. Application of the Group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) suppressed slow- and medium-duration afterhyperpolarizations (s- and mAHP) and caused a consequent increase in cell excitability as well as a depolarization of the membrane and an increase in input resistance. Interestingly, with the exception of the suppression of the mAHP, these effects were persistent, and in the case of the sAHP lasting for more than 1 h of drug washout. Preincubation with the specific mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), reduced but did not completely prevent the effects of DHPG. However, preincubation with both MPEP and the mGluR1 antagonist LY367385 completely prevented the DHPG-induced changes. These results demonstrate that the DHPG-induced changes are mediated partly by mGluR5 and partly by mGluR1. Because Group I mGluRs are linked to PLC via G-protein activation, we also investigated pathways downstream of PLC activation, using chelerythrine and cyclopiazonic acid to block protein kinase C (PKC) and inositol 1,4,5-trisphosphate-(IP3)-activated Ca2+ stores, respectively. Neither inhibitor affected the DHPG-induced suppression of the sAHP or the increase in excitability nor did an inhibitor of PLC itself, U-73122. Taken together, these results argue that in CA1 pyramidal cells in the adult rat, DHPG activates mGluRs of both the mGluR5 and mGluR1 subtypes, causing a long-lasting suppression of the sAHP and a consequent persistent increase in excitability via a PLC-, PKC-, and IP3-independent transduction pathway.

Calcium-dependent current generating the afterhyperpolarization of hippocampal neurons

1986 ◽  
Vol 55 (6) ◽  
pp. 1268-1282 ◽  
Author(s):  
B. Lancaster ◽  
P. R. Adams
Keyword(s):  
Voltage Clamp ◽  
Hippocampal Neurons ◽  
Hippocampal Slices ◽  
Outward Current ◽  
Pyramidal Cells ◽  
Resting Potential ◽  
Tail Current ◽  
Calcium Dependent ◽  
K Current

A single-electrode voltage-clamp technique was employed on in vitro hippocampal slices to examine the membrane current responsible for the slow afterhyperpolarization (AHP) in CA1 pyramidal cells. This was achieved by using conventional procedures to evoke an AHP in current clamp, followed rapidly by a switch into voltage clamp (hybrid clamp). The AHP current showed a dependence on extracellular K+, which was close to that predicted for a K+ current by the Nernst equation. The AHP current could be blocked by Cd2+ or norepinephrine. Although the AHP current showed a requirement for voltage-dependent Ca2+ entry, the current did not show any clear intrinsic voltage dependence. Once activated, AHP current is not turned off by hyperpolarizing the membrane potential. The effects of norepinephrine, Cd2+, and tetraethylammonium (TEA) were used to identify an AHP current component to the outward current evoked by depolarizing voltage commands from holding potentials that approximate to the resting potential for these cells. The AHP current can contribute significantly to the outward current during the depolarizing command. Upon repolarization it is evident as a slow outward tail current. This slow tail current had the same time constant as AHP currents evoked by hybrid clamp. Fast components to the tail currents were also observed. These were sensitive to Cd2+ and TEA. They probably represent a voltage-sensitive gKCa, sometimes termed C-current. The strong sensitivity to voltage and TEA displayed by the conventionally described gKCa (IC) are properties inconsistent with the AHP. It seems likely that the AHP current (IAHP) represents a Ca2+-activated K+ current separate from IC and that these two currents coexist in the same cell.

Evidence from simultaneous intracellular recordings in rat hippocampal slices that area CA3 pyramidal cells innervate dentate hilar mossy cells

1994 ◽  
Vol 72 (5) ◽  
pp. 2167-2180 ◽  
Author(s):  
H. E. Scharfman
Keyword(s):  
Pyramidal Cell ◽  
Action Potentials ◽  
Granule Cells ◽  
Hippocampal Slices ◽  
Pyramidal Cells ◽  
Probability Of Failure ◽  
Mossy Cells ◽  
Mossy Cell ◽  
Ca3 Pyramidal Cells ◽  
Area Ca3

1. Simultaneous intracellular recordings of area CA3 pyramidal cells and dentate hilar “mossy” cells were made in rat hippocampal slices to test the hypothesis that area CA3 pyramidal cells excite mossy cells monosynaptically. Mossy cells and pyramidal cells were differentiated by location and electrophysiological characteristics. When cells were impaled near the border of area CA3 and the hilus, their identity was confirmed morphologically after injection of the marker Neurobiotin. 2. Evidence for monosynaptic excitation of a mossy cell by a pyramidal cell was obtained in 7 of 481 (1.4%) paired recordings. In these cases, a pyramidal cell action potential was followed immediately by a 0.40 to 6.75 (mean, 2.26) mV depolarization in the simultaneously recorded mossy cell (mossy cell membrane potentials, -60 to -70 mV). Given that pyramidal cells used an excitatory amino acid as a neurotransmitter (Cotman and Nadler 1987; Ottersen and Storm-Mathisen 1987) and recordings were made in the presence of the GABAA receptor antagonist bicuculline (25 microM), it is likely that the depolarizations were unitary excitatory postsynaptic potentials (EPSPs). 3. Unitary EPSPs of mossy cells were prone to apparent “failure.” The probability of failure was extremely high (up to 0.72; mean = 0.48) if the effects of all presynaptic action potentials were examined, including action potentials triggered inadvertently during other spontaneous EPSPs of the mossy cell. Probability of failure was relatively low (as low as 0; mean = 0.24) if action potentials that occurred during spontaneous activity of the mossy cell were excluded. These data suggest that unitary EPSPs produced by pyramidal cells are strongly affected by concurrent synaptic inputs to the mossy cell. 4. Unitary EPSPs were not clearly affected by manipulation of the mossy cell's membrane potential. This is consistent with the recent report that area CA3 pyramidal cells innervate distal dendrites of mossy cells (Kunkel et al. 1993). Such a distal location also may contribute to the high incidence of apparent failures. 5. Characteristics of unitary EPSPs generated by pyramidal cells were compared with the properties of the unitary EPSPs produced by granule cells. In two slices, pyramidal cell and granule cell inputs to the same mossy cell were compared. In other slices, inputs to different mossy cells were compared. In all experiments, unitary EPSPs produced by granule cells were larger in amplitude but similar in time course to unitary EPSPs produced by pyramidal cells. Probability of failure was lower and paired-pulse facilitation more common among EPSPs triggered by granule cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Membrane Potential of CA3 Hippocampal Pyramidal Cells During Postnatal Development

2003 ◽  
Vol 90 (5) ◽  
pp. 2964-2972 ◽  
Author(s):  
Roman Tyzio ◽  
Anton Ivanov ◽  
Cristophe Bernard ◽  
Gregory L. Holmes ◽  
Yehezkiel Ben-Ari ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Postnatal Development ◽  
Developmental Change ◽  
Hippocampal Slices ◽  
Pyramidal Cells ◽  
Input Resistance ◽  
Whole Cell ◽  
Perforated Patch ◽  
Ca3 Pyramidal Cells ◽  
Whole Cell Recordings

A depolarized resting membrane potential has long been considered to be a universal feature of immature neurons. Despite the physiological importance, the underlying mechanisms of this developmental phenomenon are poorly understood. Using perforated-patch, whole cell, and cell-attached recordings, we measured the membrane potential in CA3 pyramidal cells in hippocampal slices from postnatal rats. With gramicidin perforated-patch recordings, membrane potential was –44 ± 4 (SE) mV at postnatal days P0–P2, and it progressively shifted to –67 ± 2 mV at P13–15. A similar developmental change of the membrane potential has been also observed with conventional whole cell recordings. However, the value of the membrane potential deduced from the reversal potential of N-methyl-d-aspartate channels in cell-attached recordings did not change with age and was –77 ± 2 mV at P2 and –77 ± 2 mV at P13–14. The membrane potential measured using whole cell recordings correlated with seal and input resistance, being most depolarized in neurons with high, several gigaohms, input resistance and low seal resistance. Simulations revealed that depolarized values of the membrane potential in whole cell and perforated-patch recordings could be explained by a shunt through the seal contact between the pipette and membrane. Thus the membrane potential of CA3 pyramidal cells appears to be strongly negative at birth and does not change during postnatal development.

Trans-ACPD, a metabotropic receptor agonist, produces calcium mobilization and an inward current in cultured cerebellar Purkinje neurons

1994 ◽  
Vol 71 (5) ◽  
pp. 1992-1998 ◽  
Author(s):  
D. J. Linden ◽  
M. Smeyne ◽  
J. A. Connor
Keyword(s):  
Dicarboxylic Acid ◽  
Metabotropic Glutamate Receptor ◽  
Pyramidal Cells ◽  
Purkinje Neurons ◽  
Kainate Receptors ◽  
K Channel ◽  
Racemic Mixture ◽  
Tetraacetic Acid ◽  
Metabotropic Receptor ◽  
Inward Current

1. 1-aminocyclopentane-trans-1,3-dicarboxylic acid (t-ACPD), a racemic mixture of 1-aminocyclopentane-1S,3R-dicarboxylic acid and 1-aminocyclopentane-1R,3S-dicarboxylic acid, a selective agonist of the metabotropic glutamate receptor, was applied to mouse Purkinje neurons (PNs) in culture. Measurements of free intracellular Ca2+ were made using fura-2 microfluorimetric imaging and of membrane current using perforated-patch voltage-clamp recording in separate experiments. 2. Brief pulses of t-ACPD (< or = 100 microM, 1–5 s) consistently produced a large (200–600 nM) increase in dendritic Ca2+ that was sometimes followed by a somatic increase. The dendrites typically returned to basal Ca2+ levels within 10–30 s. 3. Ca2+ increases produced by t-ACPD were measured in Ca(2+)-free external saline [0.5 mM ethylene glycol-bis(beta-amino-ethyl ether)-N,N,N',N'-tetraacetic acid (EGTA)], suggesting that they result from intracellular mobilization rather than influx. In addition, Ca2+ increases were not attenuated by a mixture of DL-AP5 and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) [antagonists of N-methyl-D-aspartate (NMDA) and AMPA/kainate receptors, respectively], but were almost entirely eliminated by L-AP3 (100 microM), a putative metabotropic receptor antagonist or by preincubation of the cultures in pertussis toxin. 4. Brief pulses of t-ACPD (10 microM) produced a small inward current that was associated with an increase in membrane conductance. This current was reversibly blocked by L-AP3 but not by treatments that attenuate some voltage-gated K+ currents. Thus this current is unlikely to underlie the depolarization that is produced by metabotropic agonists in hippocampal pyramidal cells by K(+)-channel closure. 5. The t-ACPD induced inward current was attenuated by substitution of external Na+ with Li+ or choline, or by application of the membrane-permeable Ca2+ chelator, bis-(2-aminophenoxy)-N,N,N',N'- tetraacetic acid (BAPTA)/AM. One mechanism that could mediate this current is electrogenic Nao/Cai exchange, triggered by Ca2+ mobilization.

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