| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Department of Physiology and Pharmacology, SUNY Health Science Center at Brooklyn, Brooklyn, NY 11203, USA
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
(Received 24 July 2003;
accepted after revision 21 October 2003;
first published online 24 October 2003)
Corresponding author S. R. Young: Department of Physiology and Pharmacology, SUNY Health Science Center at Brooklyn, Brooklyn, NY 11203, USA. Email: steve.young{at}downstate.edu
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
All three AHPs may be modulated by group I mGluR activity, reviewed by Anwyl (1999). IC, which mediates the fAHP, may be augmented, probably by way of Ca2+ release from intracellular stores (Fagni et al. 1991; Chavis et al. 1998; but see Hu & Storm, 1991). Both m and sAHPs are suppressed by group I mGluR agonists, leading to increased firing rates and reduced adaptation during depolarizations (Charpak et al. 1990; Ito et al. 1992; Harata et al. 1996). Activation of group I mGluRs also induces afterdepolarizations (ADPs) in addition to the intrinsic depolarizing afterpotentials previously described (Wong & Prince, 1981; Caeser et al. 1993). By supporting the occurrence of additional spikes, ADPs may convert a single-spike firing pattern to rhythmic bursting (e.g. Fig. 1A and B). All of these changes in spike afterpotentials could contribute to mGluR-induced neuronal bursting, and to the activation of synchronized epileptiform discharges in the hippocampus (Rutecki & Yang, 1997; Martin et al. 2001). Indeed, Lee et al. (2002) have shown that synaptically released glutamate prolongs epileptiform bursting by activating group I mGluRs, and a role in this for modulation of spike afterpotentials seems likely.
|
|
This study explores the suppression of the m and sAHPs and the induction of an ADP by group I mGluRs in CA3 pyramidal cells. The effect of all three of these modulatory actions is to increase the chance that a single action potential will be immediately followed by additional spikes, thus generating bursts (Fig. 1). We show that the appearance of an ADP is independent of the blockade of the AHP and that it is voltage-dependent, being suppressed at hyperpolarized levels. The role of [Ca2+]in increases in linking mGluRs to afterpotential modulation is also examined. In Ca2+ imaging experiments combined with intracellular recording, we find that neither the appearance of an ADP nor suppression of the AHP is correlated with any changes in Ca2+ transients following action potentials. In experiments using PLCß1 knockout mice, we show that mGluR-mediated suppression of the mAHP, as well as appearance of the ADP, is dependent on the phosphoinositide (PI) hydrolysis pathway, while mGluR block of the sAHP is, at least in part, independent of PLC.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The preparation of transverse hippocampal slices (about 300 µm thick) from adult guinea pigs has been described in detail previously (Bianchi & Wong, 1995). In brief, guinea pigs were anaesthetized by halothane inhalation in conformity with the guidelines of the Institutional Animal Care and Use Committee (protocol number 9808069). They were then decapitated, hippocampi were removed, and slices cut in ice-cold artificial cerebro-spinal fluid (aCSF; see below) with a Vibratome (Technical Products International, St Louis, MO, USA). Slices were stored at room temperature in aCSF for at least 1 hour prior to use. One slice at a time was submerged in a recording chamber with a cover slip bottom and superfused at 3–5 ml per minute, also with aCSF. Temperature was maintained at 31 ± 1°C. The composition of aCSF was (in mM) 124 NaCl, 26 NaHCO3, 5 KCl, 1.6 MgCl2, 2.0 CaCl2 and 10 D-glucose. The pH was maintained at 7.4 by continuous bubbling with 95% O2/5% CO2. Low Ca2+/Mn2+ solution, used to suppress voltage-dependent Ca2+ entry (Wong & Prince, 1981), had the same composition except that CaCl2 was reduced to 0.2 mM, and 0.5-mM MnCl2 was added. Slices were held against the bottom of the recording chamber with nylon threads stretched across a platinum ring. This arrangement provided mechanical stability but did not prevent solution exchange at the bottom of the slice. The recording chamber was fixed in a steel plate mounted on the mechanical stage of a Nikon Diaphot inverted microscope. Micromanipulators holding electrodes, perfusion tubing, etc. were fixed magnetically to the same plate.
Mice lacking phospholipase Cß1 (PLCß1-/-Kim et al. 1997) were obtained and maintained as previously described (Chuang et al. 2001). PLCß1-/- mice and wild-type littermates were genotyped by PCR as previously described (Kim et al. 1997). Hippocampal slices from mice were obtained and treated in the same way as the guinea pig slices (see above).
Animal use procedures were approved by the SUNY Downstate Animal Care and Use Committee.
Electrophysiological and optical recordings
Electrophysiological and optical recording techniques have been previously described (Bianchi et al. 1999; Young et al. 2000). Current clamp recordings were made from CA3 (or CA1 in Fig. 5A) pyramidal cells using glass micropipettes. Pipettes were pulled from thin-walled capillaries (WPI, TW100F), filled with 2 M potassium acetate, and typically had resistances of 25–40 M
. For optical recordings, pipettes were filled with 0.4 M potassium acetate and 0.5 mM calcium green-1 (C3010, Molecular Probes, Eugene, OR, USA) and had resistances of 50–80 M. Recordings were amplified with an Axoclamp 2B (Axon Instruments, Union City, CA, USA), displayed on an oscilloscope (DSO 400, Gould, Valley View, OH, USA) and chart recorder (Gould TA240), and stored on FM tape (Store 4DS, Racal, Southampton, UK). Recordings were also filtered (8-pole Bessel, –3 dB typically 1 kHz), and sampled (pCLAMP, TL-1, Axon Instruments, 3–5 kHz) for storage and subsequent analysis by computer. Intracellular square-wave current pulses were applied by the Axoclamp as triggered by a digital stimulator (PG 4000, Neuro Data Instruments, New York, NY, USA). Hyperpolarizing pulses (–0.2 to –0.5 nA, 150 ms) were applied throughout to monitor the condition of the cell membrane and adjust the bridge balance.
|
F/F: Bianchi et al. 1999; Young et al. 2000). Cells were accepted for optical recording only if their response (F/F) to brief trains of action potentials was greater than 10%. Very few cells failed this criterion; however, rare cells were encountered in the pyramidal cell layer that appeared round rather than pyramidal, exhibited very little spike frequency adaptation, and had little or no voltage-dependent calcium response. These cells were not included here. Pharmacological agents
To eliminate contributions from ionotropic glutamate receptors, a control solution was used in which 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 µM) and 3-((R, S)-2-carboxypiperazin-4-yl)-propyl-1-phosophonic acid (CPP, 20 µM) were added to the aCSF. The specific group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG, 10–50 µM) was applied by addition to the bathing solution. Slices were kept in DHPG for at least 5 min before data were taken to allow time for responses to stabilize. Tetraethylammonium chloride (TEA, 2–5 mM) was used to block the IM component of the mAHP (Lancaster & Adams, 1986). DHPG, CNQX and CPP were purchased from Tocris Cookson (Ballwin, MO, USA). The broad spectrum PLC inhibitor U73122 was purchased from Calbiochem (La Jolla, CA, USA). All other chemicals were from Sigma (St Louis, MO, USA).
Curve fitting and statistics
Exponential fits were obtained to both optical and membrane voltage traces using the Chebyshev method in the Clampfit (version 6.0.4, Axon Instruments) component of the pCLAMP package. The Ca2+ decay data of Fig. 9 were fitted with exponential curves of one, two or three components. Single exponential fits were poor, diverging markedly from the data. Third-order fits were not consistent, yielding wildly varying parameters from one trace to the next. Second-order fits were stable and consistent. Moreover, the two time constants that we obtained, roughly 100–200 ms for the fast component and 500–1000 ms for the slow, appeared to correspond to the two buffers used in the model of Sala & Hernandez-Cruz (1990), namely B1 representing fast, mobile cytosolic buffers and B2 representing uptake by the endoplasmic reticulum. Fits are described by time constant (
), amplitude (a) and standard deviation (s).
|
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
However, under otherwise unchanged pharmacological conditions and with membrane potential held constant with hyperpolarizing current, DHPG frequently induced burst firing in cells that had been spontaneously firing single action potentials. Figure 1A shows a CA3 pyramidal cell firing spontaneously in aCSF (see Methods). After addition of 10 µM DHPG, single action potentials were replaced by short bursts of two to three spikes. In another cell (Fig. 1B), low Ca2+/Mn2+ solution (see Methods) was used to block Ca2+-dependent synaptic transmission. Addition of DHPG also elicited bursting under this condition, suggesting that the switch to burst firing did not depend on excitatory synaptic events. Group I mGluRs are linked by G proteins to PLC (see below). Figure 1C shows a cell firing spontaneously in U73122, a broad-spectrum PLC inhibitor that could be expected to block some or all of the effects of DHPG. Addition of DHPG increased the firing rate, signalling a reduction of the sAHP, but it did not completely eliminate the mAHP, and it did not induce bursting.
To examine the changes underlying the altered firing pattern in more detail, we suppressed spontaneous activity by hyperpolarizing the cells, and blocked recurrent glutamatergic transmission with CNQX and CPP (control solution, see Methods). We then triggered either repetitive action potentials, with 100 ms depolarizations, or single spikes with 10 ms pulses. In Fig. 2A, a depolarizing current injection produced a strongly adapting burst of action potentials followed by a pronounced hyperpolarization. After addition of 10 µM DHPG, spike frequency adaptation was greatly reduced and the AHP was nearly eliminated. Single action potentials activated with 10 ms depolarizing pulses were then examined (Fig. 2B). AHPs were monitored following single action potentials by averaging multiple sweeps. The average amplitude of AHPs following single action potentials was –2.0 ± 1 mV at peak (230 ± 96 ms following depolarizing pulse; four cells at –60 mV), which included both m and sAHPs. sAHPs were measured at 700 ms postpulse, at which time there was little or no contribution from the mAHP (four measurements of averaged sweeps of mAHPs isolated using low Ca2+/Mn2+ solution (see below), decayed to half peak amplitude in 185 ± 53 ms postpulse). sAHPs (at 700 ms) averaged –1.0 ± 0.3 mV and returned to baseline in 2.8 s (±0.9 s, n= 4 at –60 mV). In 10 µM DHPG, hyperpolarizing current was added to counteract the depolarization elicited by mGluR activation (Bianchi et al. 1999). Postspike AHPs were absent and were reversibly replaced by afterdepolarizations in eight out of nine cells. ADPs in four cells measured at –64 mV averaged 2.5 mV (±1.5 mV; at 150 ms postpulse) and returned to baseline in 810 ms (±600 ms).
|
The above experiments did not determine whether the ADP was induced by mGluR activation or if it appeared indirectly, via suppression of the AHP. This question was addressed by the experiments shown in Fig. 3A. Single action potentials were stimulated by 10 ms depolarizing pulses. Sixteen sweeps were averaged for each panel. Following action potentials in control solution, the cell rapidly repolarized and hyperpolarized by about 1 mV. The AHP was sustained for several tens of milliseconds and then slowly decayed over the next second. Introduction of low Ca2+/Mn2+ solution to block voltage-dependent Ca2+ entry during the action potential (Methods; second panel, Fig. 3A) suppressed the Ca2+-dependent AHP. The remaining sharp repolarization and undershoot following the spike (mAHP) were blocked by addition of TEA, as shown in the third panel of Fig. 3A. However, blocking both medium and slow components of the AHP did not produce an ADP. The fourth panel of Fig. 3A shows that, in low Ca2+/Mn2+ solution with 2 mM TEA, the ADP appeared only after DHPG was added to the bath. Frequently, one or two additional action potentials rode the ADP and appear in the averaged trace. Figure 3B shows a different cell with single traces superimposed without averaging and at a higher sweep speed. The falling phase of the action potential in the absence of DHPG was well described by a single-component exponential decay (= 20.36 ms, A= 20.06 mV, s= 0.29 mV, n= 15), suggesting that repolarization after a spike in low Ca2+/Mn2+ and TEA was largely passive. The ADP induced by DHPG in this cell is shown as well. In a total of four experiments using both Mn2+ and TEA to block the AHP, and in other experiments using either Mn2+ or TEA, an ADP did not appear until DHPG was added. These experiments demonstrated that the appearance of an ADP in the presence of mGluR agonists was not merely due to unmasking following block of the AHP. It should be further noted that the ADP persisted in low Ca2+/Mn2+ recording solution, showing that the appearance of the ADP did not require voltage-dependent Ca2+ influx. The ADP thus resulted from activation of a membrane current, other than a voltage-gated Ca2+ current that was elicited by mGluR stimulation.
The ADP also appeared to be voltage-dependent. Since virtually all cells required hyperpolarizing current to suppress spontaneous activity when exposed to DHPG, recording the ADP was largely a matter of balancing suppression of spontaneous activity against suppression of the ADP at hyperpolarized levels. This is illustrated in Fig. 4. In control solution, hyperpolarization reduced the size of the AHP. Introduction of low Ca2+/Mn2+ solution containing TEA blocked the AHP. Under these conditions, addition of DHPG induced an ADP that was prominently expressed at –63 mV, and that was blocked at –70 mV.
|
Role of PLC
Group I mGluR activity is strongly linked to stimulation of PLC and phosphoinositide hydrolysis (Conn & Pin, 1997). However, not all effects of group I mGluRs are mediated by PLC activity. In particular, Ireland & Abraham (2002) have reported that the broad-spectrum PLC blocker U-73122 did not prevent DHPG suppression of the sAHP in CA1 pyramidal cells. Krause et al. (2002) also found that sAHPs were still present, although suppressed about 50% by DHPG in CA1 pyramidal cells of mice lacking G
q. We made use of a mutant mouse strain lacking phospholipase Cß1 (PLCß1-/-, PLC knockouts: Kim et al. 1997) to determine which of the observed alterations of spike afterpotentials, i.e. suppression of the mAHP, suppression of the sAHP and induction of an ADP, might be dependent on the inositol phosphate transduction pathway. Figure 6A shows AHPs following bursts of action potentials recorded from a CA3 pyramidal cell in a slice taken from a PLCß1 knockout mouse. DHPG reversibly reduced, but did not eliminate, the AHP. The average reduction in sAHP amplitude by DHPG was 54 ± 27% (measured at 700 ms after the pulse, control AHP was –3.2 ± 2.7 mV, n= 8; in DHPG, the AHP was –1.4 ± 1.1 mV, n= 8; P= 0.03, Student's paired t test). AHPs in wild-type mice were nearly eliminated by DHPG, as in guinea pigs (data not shown). Blocking Ca2+ influx in slices from PLCß1 knockouts by perfusing low Ca2+/Mn2+ solution (Fig. 6B, second panel) eliminated most of the sAHP, as in normal animals, while sparing the voltage-sensitive but Ca2+-insensitive component of the mAHP. However, contrary to our observations with normal animals, application of up to 50 µM DHPG neither suppressed the mAHP nor elicited an ADP (Fig. 6B, third panel).
|
Involvement of Ca2+
Previous investigators have reported that mGluR suppression of the AHP was not mediated by reduction of spike-induced [Ca2+]in transients (Charpak et al. 1990). In order to confirm that finding, and to explore the role of Ca2+ in generating the ADP, we recorded from CA3 pyramidal cells with electrodes containing the Ca2+-sensitive dye calcium green-1, and monitored [Ca2+]in simultaneously with mGluR modulation of spike afterpotentials (Fig. 7). Simultaneous recordings of [Ca2+]in and Vm following single spikes from before, during and after DHPG exposure showed that the amplitude of spike-induced Ca2+ entry was not affected by the presence or absence of DHPG. In six pyramidal cells, a total of 10 measurements were made of Ca2+ transient amplitudes following single spikes in control solution, and seven measurements were made in 10 µM DHPG (16 sweeps averaged per measurement). Membrane potential was maintained throughout the measurements in each cell by manual adjustment of injected current. Basal fluorescence (F) often increased somewhat over time in a given cell. However, the order of measurements was balanced so that DHPG measurements followed control measurements six times and control followed DHPG five times. The average basal F was 314 ± 193 (analog-to-digital converter units) in control and 274 ± 178 in DHPG. The average amplitude of postspike Ca2+ transients was 14.5 ± 4.0% in control (F/F; n= 10) and 14.3 ± 3.6% in DHPG (n= 7). Eleven comparisons within each of the six cells of the percentage change in the Ca2+ transient amplitude between control and DHPG (peak Ca2+ rise in control minus peak Ca2+ rise in DHPG, normalized to peak Ca2+ rise in control) averaged 3.3 ± 18.3%. Additional experiments in PLCß1–/– mice showed, similarly, that spike-induced [Ca2+]in transients were unchanged by DHPG (data not shown).
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
sAHP suppression
The major conclusion of our experiments on the transduction pathway linking group I mGluR activation to suppression of the sAHP is that, since DHPG reversibly reduced the sAHP in mice lacking PLCß1 (Fig. 6A), a mechanism that does not involve PLCß1 must be involved. However, in contrast to the nearly complete suppression of the AHP in normal animals (Fig. 2), in the absence of PLCß1 the AHP was suppressed only to 54% (±27%) of control. This suggests that a transduction pathway involving PLC does link mGluRs to AHP suppression, but that another transduction pathway is also involved.
mGluRs 1 and 5, which are selectively activated by DHPG, are coupled by Gq to PLCß1 (Masu et al. 1991; Houamed et al. 1991; Tanabe et al. 1992; Pin & Bockaert, 1995; Pin & Duvoisin, 1995; Saugstad et al. 1996; Rebecchi & Pentyala, 2000). There are a number of reports that reduction of the AHP by mGluR activity is G protein mediated (Abdul-Ghani et al. 1996; Heuss et al. 1999; Krause et al. 2002), although Krause et al. (2002) found that only about half of AHP suppression was lost in mice lacking Gq. In dentate gyrus neurones, PLC was involved in AHP suppression by mGluRs (Abdul-Ghani et al. 1996), but in CA1 cells it was not (Ireland & Abraham, 2002). This apparent diversity of results regarding the mGluR suppression of the AHP may result from a variety of different mechanisms with varying importance in different cell types. At least in two cell types, CA1 (Krause et al. 2002) and CA3 pyramidal cells (this study), multiple mechanisms apparently coexist in the same cell, since about half (but only half) of the AHP suppression is independent of pathways requiring Gq or PLC.
There may be at least three alternatives to the Gq/PLC transduction pathway in AHP suppression. First, Gß/
subunits can modulate ion channel activity independently of G (reviewed by Hepler & Gilman, 1992; Clapham & Neer, 1997). For example, ß/ subunits are required for syntaxin modulation of a voltage-gated K+ channel in oocytes (Michaelevski et al. 2002). Secondly, so-called ‘promiscuous coupling’ of group I mGluRs to G proteins other than Gq occurs in expression systems and may be physiologically relevant (reviewed by Hermans & Challiss, 2001). A third possibility is G-protein-independent coupling of mGluRs to second messenger pathways (Heuss & Gerber, 2000). Heuss et al. (1999) proposed a G-protein-independent tyrosine kinase-dependent pathway for an mGluR1-mediated mossy fibre EPSC, although they also found that inhibiting G-protein function with GDPßS partly inhibited mossy fibre induced AHP suppression.
mAHP suppression
The mAHP results from a number of currents (Halliwell & Adams, 1982; Storm, 1989; Alger et al. 1990; Stocker et al. 1999; Sailer et al. 2002; Sah & Faber, 2002), including at least the voltage-dependent IM, which is known to be blocked by group I mGluRs (Charpak et al. 1990; Pin & Duvoisin, 1995; Anwyl, 1999), and the Ca2+-activated IAHP. In the absence of a specific blocker for the mGluR-stimulated ADP, we cannot rule out the possibility that some of the mGluR suppression of the mAHP in CA3 was due to masking by the ADP. However, in CA1, the AHP was nearly eliminated by DHPG despite the lack of a mGluR-stimulated ADP (Fig. 5). Since the Ca2+-activated IAHP is not thought to be modulated by neurotransmitters (Stocker et al. 1999), these results support the conclusion that IM is the major component of the mAHP in the hippocampus. Thus the failure of DHPG to block the mAHP in PLCß1-/- mice, in contrast to the sAHP (Fig. 6B), suggests that the transduction pathway linking mGluR activation to suppression of IM probably requires PLC. This is consistent with the report by Suh & Hille (2002) that PLC is required for muscarinic receptor-mediated inhibition of IM since, like mGluRs, muscarinic M1 receptors couple to PLC by way of Gq/11 proteins.
ADP induction
We also investigated possible mechanisms for the group I mGluR induction of an ADP. Experiments involving blocking of the m and sAHPs (by Mn2+ and TEA, Fig. 3A) showed that the ADP was not an intrinsic event unmasked by AHP blockade.
In mouse hippocampal slices lacking PLCß1, ADPs could not be induced (Fig. 6B) using up to 50 µM DHPG. This argued against a role for the G-protein-independent current described by Heuss et al. (1999). On the other hand, the importance of PLC also suggested that Ca2+ release might have a role in ADP generation, particularly in view of the Ca2+ dependence of the ADP reported by Caeser et al. (1993) in hippocampal slice cultures. However, our data make two points that argue against a role for modulation of [Ca2+]in in the appearance of the mGluR-induced ADP in CA3. First, the low Ca2+/Mn2+ solution used to block voltage-dependent Ca2+ influx did not prevent induction of an ADP by DHPG (Figs 3 and 4). Secondly, there was no correlation between the amplitude or the time course of the spike-induced [Ca2+]in transient and the appearance of an ADP (Figs 7 and 8).
Large additions to postspike [Ca2+]in transients due to release from intracellular stores have been described by Nakamura et al. (1999). The release was stimulated by mGluR activation and was augmented by multiple spikes. We attempted to elicit such release by increasing the number of action potentials in a burst from one to three. However, careful analysis of [Ca2+]in decay curves (Fig. 9) failed to show any additional components of postspike [Ca2+]in transients as a result of DHPG-induced intracellular release. This could have been due to our use of the high-affinity Ca2+ dye calcium green-1 (Nakamura et al. 2000). Perhaps more important was that we did not ‘refill’ Ca2+ stores during an experiment, as has been proven necessary to demonstrations of Ca2+ release in numerous studies (Jaffe et al. 1994; Pozzo-Miller et al. 1996; Berridge, 1998). The fact remains that DHPG-induced ADPs in CA3 were elicited in the absence of any changes in the [Ca2+]in rise following an action potential.
What current underlies the ADP?
Several properties of the mGluR-induced ADP in CA3 pyramidal cells help to set limits on which currents could underlie the potential. The ADP was voltage-dependent, having a threshold near –70 mV. It could not be elicited in the absence of PLCß1-/-, and it did not depend on alterations of the postspike [Ca2+]in transient. The non-specific cation current reported by Guérineau et al. (1995) was neither voltage- nor Ca2+-sensitive, so is unlikely to produce a postspike ADP. The CAN current reported by Caeser et al. (1993) was activated at a membrane potential similar to the potential at which we found the mGluR-induced ADP appearing. However, in contrast to that study, we found that divalent cation block of voltage-dependent Ca2+ entry did not block the ADP (Figs 3 and 4). Nor did DHPG-induction of the ADP correlate with any changes in spike-induced [Ca2+]in increases (Figs 7 and 8).
An inward current in CA3 that was associated with a conductance increase has been described by this laboratory (ImGluR(V); Chuang et al. 2000). ImGluR(V) has both the voltage sensitivity and resistance to Ca2+ channel blockers required to produce the ADP. Further, both ImGluR(V) and the ADP require PLCß1 for induction (Chuang et al. 2002). A final point of similarity is the occurrence of mGluR-induced ADPs in CA3, but not in CA1, which matches the hippocampal distribution of ImGluR(V) (Chuang et al. 2002). Taken together, these points suggest that group I mGluR activity induces a postspike ADP that is carried by ImGluR(V).
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Aldrich RW, Getting PA & Thompson SH (1979). Mechanism of frequency-dependent broadening of molluscan neurone soma spikes. J Physiol 291, 531–544.
Alger BE, Pitler TA & Williamson A (1990). A prolonged post-tetanic hyperpolarization in rat hippocampal pyramidal cells in vitro. Brain Res 521, 118–124.[CrossRef][Medline]
Andrew RD & Dudek FE (1984). Intrinsic inhibition in magnocellular neuroendocrine cells of rat hypothalamus. J Physiol 353, 171–185.
Anwyl R (1999). Metabotropic glutamate receptors: electrophysiological properties and role in plasticity. Brain Res Rev 29, 83–120.[CrossRef][Medline]
Baraban JM, Snyder SH & Alger BE (1985). Protein kinase C regulates ionic conductance in hippocampal pyramidal neurons: electrophysiological effects of phorbol esters. Proc Natl Acad Sci U S A 82, 2538–2542.
Berridge MJ (1998). Neuronal calcium signaling. Neuron 21, 13–26.[CrossRef][Medline]
Beurrier C, Congar P, Bioulac B & Hammond C (1999). Subthalamic nucleus neurons switch from single-spike activity to burst-firing mode. J Neurosci 19, 599–609.
Bianchi R & Wong RKS (1995). Excitatory synaptic potentials dependent on metabotropic glutamate receptor activation in guinea-pig hippocampal pyramidal cells. J Physiol 487, 663–676.
Bianchi R, Young SR & Wong RKS (1999). Group I metabotropic glutamate receptor activation causes both voltage-independent and voltage-dependent intracellular calcium increases in CA1 and CA3 neurons of hippocampal slices. J Neurophysiol 81, 2903–2913.
Caeser M, Brown DA, Gahwiler BH & Knopfel T (1993). Characterization of a calcium-dependent current generating a slow afterdepolarization of CA3 pyramidal cells in rat hippocampal slice cultures. Eur J Neurosci 5, 560–569.[CrossRef][Medline]
Charpak S, Gähwiler BH, Do KQ & Knöpfel T (1990). Potassium conductances in hippocampal neurons blocked by excitatory amino acid transmitters. Nature 347, 765–767.[CrossRef][Medline]
Chavis P, Ango F, Michel JM, Bockaert J & Fagni L (1998). Modulation of big K+ channel activity by ryanodine receptors and L-type Ca2+ channels in neurons. Eur J Neurosci 10, 2322–2327.[CrossRef][Medline]
Chuang SC, Bianch R, Kim D, Shin H-S & Wong RKS (2001). Group I metabotropic glutamate receptors elicit epileptiform discharges in the hippocampus through PLCB1 signaling. J Neurosci 21, 6387–6394.
Chuang SC, Bianchi R & Wong RKS (2000). Group I mGluR activation turns on a voltage-dependent inward current in hippocampal pyramidal cells. J Neurophysiol 83, 2844–2853.
Chuang SC, Zhao W, Young SR, Conquet F, Bianchi R & Wong RKS (2002). Activation of group I mGluRs elicits different responses in murine CA1 and CA3 pyramidal cells. J Physiol 541, 113–121.
Clapham DE & Neer EJ (1997). G protein beta gamma subunits. Annu Rev Pharmacol Toxicol 37, 167–203.[CrossRef][Medline]
Congar P, Leinekugel X, Ben-Ari Y & Crepel V (1997). A long-lasting calcium-activated nonselective cationic current is generated by synaptic stimulation or exogenous activation of group I metabotropic glutamate receptors in CA1 pyramidal neurons. J Neurosci 17, 5366–5379.
Conn PJ & Pin J-P (1997). Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmaco1 Toxicol 37, 205–237.[CrossRef]
Fagni L, Bossu JL & Bockaert J (1991). Activation of a large-conductance Ca2+-dependent K+ channel by stimulation of glutamate phosphoinositide-coupled receptors in cultured cerebellar granule cells. Eur J Neurosci 3, 778–789.[CrossRef][Medline]
Gerber U, Sim JA & Gahwiler BH (1992). Reduction of potassium conductances mediated by metabotropic glutamate receptors in rat CA3 pyramidal cells does not require protein kinase C or protein kinase A. Eur J Neurosci 4, 792–797.[CrossRef][Medline]
Gereau RWI & Conn PJ (1994). A cyclic AMP-dependent form of associative synaptic plasticity induced by coactivation of beta-adrenergic receptors and metabotropic glutamate receptors in rat hippocampus. J Neurosci 14, 3310–3318.[Abstract]
Gereau RWI, Winder DG & Conn PJ (1995). Pharmacological differentiation of the effects of co-activation of ß-adrenergic and metabotropic glutamate receptors in rat hippocampus. Neurosci Lett 186, 119–122.[CrossRef][Medline]
Goh JW, Kelly ME, Pennefather PS, Chicchi GG, Cascieri MA, Garcia ML & Kaczorowski GJ (1992). Effect of charybdotoxin and leiurotoxin I on potassium currents in bullfrog sympathetic ganglion and hippocampal neurons. Brain Res 591, 165–170.[CrossRef][Medline]
Greene CC, Schwindt PC & Crill WE (1994). Properties and ionic mechanisms of a metabotropic glutamate receptor-mediated slow afterdepolarization in neocortical neurons. J Neurophysiol 72, 693–704.
Guatteo E, Mercuri NB, Bernardi G & Knopfel T (1999). Group I metabotropic glutamate receptors mediate an inward current in rat substantia nigra dopamine neurons that is independent from calcium mobilization. J Neurophysiol 82, 1974–1981.
Guérineau NC, Bossu JL, Gahwiler BH & Gerber U (1995). Activation of nonselective cationic conductance by metabotropic glutamatergic and muscarinic agonists in CA3 pyramidal neurons of the rat hippocampus. J Neurosci 15, 4395–4407.[Abstract]
Halliwell JV & Adams PR (1982). Voltage-clamp analysis of muscarinic excitation in hippocampal neurons. Brain Res 250, 71–92.[CrossRef][Medline]
Harata N, Katayama J, Takeshita Y, Murai Y & Akaike N (1996). Two components of metabotropic glutamate responses in acutely dissociated CA3 pyramidal neurons of the rat. Brain Res 711, 223–233.[CrossRef][Medline]
Hepler JR & Gilman AJ (1992). G proteins. Trends Biol Sci 17, 383–387.[CrossRef]
Hermans E & Challiss RA (2001). Structural, signalling and regulatory properties of the group I metabotropic glutamate receptors: prototypic family C G-protein-coupled receptors. Biochem J 359, 465–484.[CrossRef][Medline]
Heuss C & Gerber U (2000). G-protein-independent signaling by G-protein-coupled receptors. Trends Neurosci 23, 469–475.[CrossRef][Medline]
Heuss C, Scanziani M, Gahwiler BH & Gerber U (1999). G-protein independent signaling mediated by metabotropic glutamate receptors. Nature Neurosci 2, 1070–1077.[CrossRef][Medline]
Hotson JR & Prince DA (1980). A calcium activated hyperpolarization follows repetitive firing in hippocampal neurons. J Neurophysiol 43, 409–419.
Houamed KM, Kuijper JL, Gilbert TL, Haldeman BA, O'Hara PJ, Mulvihill ER, Almers W & Hagen FS (1991). Cloning, expression, and gene structure of a G protein-coupled glutamate receptor from rat brain. Science 252, 1318–1321.
Hu G-Y & Storm JF (1991). Excitatory amino acids acting on metabotropic glutamate receptors broaden the action potential in hippocampal neurons. Brain Res 568, 339–344.[CrossRef][Medline]
Ireland DR & Abraham WC (2002). Group I mGluRs increase excitability of hippocampal CA1 pyramidal neurons by a PLC-independent mechanism. J Neurophysiol 88, 107–116.
Ito I, Kohda A, Tanabe S, Hirose E, Hayashi M, Mitsunaga S & Sugiyama H (1992). 3,5-Dihydroxyphenyl-glycine: a potent agonist of metabotropic glutamate receptors. Neuroreport 3, 1013–1016.[Medline]
Jaffe DB, Ross WN, Lisman JE, Lasser-Ross N, Miyakawa H & Johnston D (1994). A model for dendritic Ca2+ accumulation in hippocampal pyramidal neurons based on fluorescence imaging measurements. J Neurophysiol 71, 1065–1077.
Kim D, Jun KS, Lee SB, Kang NG, Min DS, Kim YH, Ryu SH, Suh PG & Shin HS (1997). Phospholipase C isozymes selectively coupled to specific neurotransmitter receptors. Nature 389, 290–293.[CrossRef][Medline]
Krause M, Offermanns S, Stocker M & Pedarzani P (2002). Functional specificity of G alpha q and G alpha 11 in the cholinergic and glutamatergic modulation of potassium currents and excitability in hippocampal neurons. J Neurosci 22, 666–673.
Lancaster B & Adams PR (1986). Calcium-dependent current generating the afterhyperpolarization of hippocampal neurons. J Neurophysiol 55, 1268–1282.
Lancaster B & Nicoll RA (1987). Properties of two calcium-activated hyperpolarizations in rat hippocampal neurones. J Physiol 389, 187–203.
Lasser-Ross N, Miyakowa H, Lev-Ram V, Young SR & Ross WN (1991). High time resolution fluorescence imaging with a CCD camera. J Neurosci Meth 36, 253–261.[CrossRef][Medline]
Lee AC, Wong RKS, Chuang S-C, Shin H-S & Bianchi R (2002). Role of synaptic metabotropic glutamate receptors in epileptiform discharges in hippocampal slices. J Neurophysiol 88, 1625–1633.
Linden DJ, Smeyne M & Connor JA (1994). Trans-ACPD, a metabotropic receptor agonist, produces calcium mobilization and an inward current in cultured cerebellar Purkinje neurons. J Neurophysiol 71, 1992–1998.
McBain CJ, DiChiara TJ & Kauer JA (1994). Activation of metabotropic glutamate receptors differentially affects two classes of hippocampal interneurons and potentiates excitatory synaptic transmission. J Neurosci 14, 4433–4445.[Abstract]
Magee JC & Carruth M (1999). Dendritic voltage-gated ion channels regulate the action potential firing mode of hippocampal CA1 pyramidal neurons. J Neurophysiol 82, 1895–1901.
Martin ED, Araque A & Buno W (2001). Synaptic regulation of the slow Ca2+-activated K+ current in hippocampal CA1 pyramidal neurons: implication in epileptogenesis. J Neurophysiol 86, 2878–2886.
Masu M, Tanabe Y, Tsuchida K, Shigemoto R & Nakanishi S (1991). Sequence and expression of a metabotropic glutamate receptor. Nature 349, 760–765.[CrossRef][Medline]
Michaelevski I, Chikvashvili D, Tsuk S, Fili O, Lohse MJ, Singer-Lahat D & Lotan I (2002). Modulation of a brain voltage-gated K+ channel by syntaxin 1A requires the physical interaction of Gß with the channel. J Biol Chem 277, 34909–34917.
Nakamura T, Barbara J-G, Nakamura K & Ross WN (1999). Synergistic release of Ca2+ from IP3-sensitive stores evoked by synaptic activation of mGluRs paired with backpropoagating action potentials. Neuron 24, 727–737.[CrossRef][Medline]
Nakamura T, Nakamura K, Lasser-Ross N, Barbara J-G, Sandler VM & Ross WN (2000). Inositol 1,4,5-trisphosphate (IP3)-mediated Ca2+ release evoked by metabotropic agonists and backpropagating action potentials in hippocampal CA1 pyramidal neurons. J Neurosci 20, 8365–8376.
Pedarzani P & Storm JF (1993). PKA mediates the effects of monoamine transmitters on the K+ current underlying the slow spike frequency adaptation in hippocampal neurons. Neuron 11, 1023–1035.[CrossRef][Medline]
Pin J-P & Bockaert J (1995). Get receptive to metabotropic glutamate receptors. Curr Opin Neurobiol 5, 342–349.[CrossRef][Medline]
Pin J-P & Duvoisin R (1995). Review: Neurotransmitter receptors I – The metabotropic glutamate receptors: structure and functions. Neuropharmacol 34, 1–26.[CrossRef][Medline]
Pozzo-Miller LD, Petrozzino JJ, Golarai G & Connor JA (1996). Ca2+ release from intracellular stores induced by afferent stimulation of CA3 pyramidal neurons in hippocampal slices. J Neurophysiol 76, 554–562.
Rebecchi MJ & Pentyala SN (2000). Structure, function and control of phospholipase C. Physiol Rev 80, 1291–1335.
Rutecki PA & Yang Y (1997). Metabotropic glutamate receptor activation modulates epileptiform activity in the hippocampus. Neurosci 81, 927–935.[CrossRef][Medline]
Sah P (1996). Ca2+-activated K+ currents in neurones: types, physiological roles and modulation. Trends Neurosci 19, 150–154.[CrossRef][Medline]
Sah P & Faber ESL (2002). Channels underlying neuronal calcium-activated potassium currents. Prog Neurobiol 66, 345–353.[CrossRef][Medline]
Sah P & McLachlan EM (1992). Potassium currents contributing to action potential repolarization and the afterhyperpolarization in rat vagal motoneurons. J Neurophysiol 68, 1834–1841.
Sailer CA, Hu H, Kaufmann WA, Trieb M, Schwarzer C, Storm JF & Knaus H-G (2002). Regional differences in distribution and functional expression of small-conductance Ca2+-activated K+ channels in rat brain. J Neurosci 22, 9698–9707.
Sala F & Hernandez-Cruz A (1990). Calcium diffusion modeling in a spherical neuron. Relevance of buffering properties. Biophys J 57, 313–324.
Saugstad JA, Segerson TP & Westbrook GL (1996). Metabotropic glutamate receptors activated G protein-coupled inwardly rectifying potassium channel in Xenopus oocytes. J Neurosci 16, 5979–5985.
Shirasaki T, Harata N & Akaike N (1994). Metabotropic glutamate response in acutely dissociated hippocampal CA1 pyramidal neurones of the rat. J Physiol 475, 439–453.
