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1 Department of System Neuroscience, Tokyo Metropolitan Institute for Neuroscience, Fuchu, Tokyo 183-8526, Japan2 CREST, Japan Science and Technology Corporation, Kawaguchi, Saitama 332-0012, Japan3 The Japan Society for the Promotion of Science, Chiyoda-ku, Tokyo 102-8471, Japan
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Abstract |
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(Received 16 December 2003;
accepted after revision 22 April 2004;
first published online 23 April 2004)
Corresponding author Y. Isomura: Department of System Neuroscience, Tokyo Metropolitan Institute for Neuroscience, 2-6 Musashidai, Fuchu, Tokyo 183-8526, Japan. Email: isomura{at}tmin.ac.jp
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Introduction |
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Several pharmacological studies suggested that GABAergic transmission might essentially contribute to the generation of this afterdischarge (Higashima et al. 1996; Klapstein & Colmers, 1997; Perez Velazquez & Carlen, 1999; Higashima et al. 2000). As an intense GABAA receptor activation during the tetanization occasionally makes the GABAA response depolarizing in mature hippocampal pyramidal cells (Alger & Nicoll, 1979; Andersen et al. 1980; Grover et al. 1993; Staley et al. 1995; Perkins & Wong, 1996; Kaila et al. 1997; Smirnov et al. 1999; Staley & Proctor, 1999; Isomura et al. 2003b) and interneurones (Lamsa & Taira, 2003), it is quite possible that GABAA-mediated excitation, rather than inhibition, may be involved in neuronal synchronization of the afterdischarge. In fact, our previous study has shown that each cycle of the afterdischarge is directly driven by excitatory GABAergic transmission per se in mature hippocampal pyramidal cells (Fujiwara-Tsukamoto et al. 2003).
On the other hand, it has been assumed that glutamatergic transmission mediated through the AMPA-type and NMDA-type receptors is also required for afterdischarge generation within a local network of the hippocampal CA1 region (Fujiwara-Tsukamoto et al. 2003), as well as for its propagation into other hippocampal regions (Isomura et al. 2003a). The pyramidal cells are the only (or major) glutamatergic neurones in the hippocampal CA1 region, and a number of GABAergic interneurones are innervated by the recurrent collaterals of the pyramidal cells in this region (Freund & Buzsáki, 1996). Therefore, synaptic interactions between the glutamatergic pyramidal cells and the GABAergic interneurones would play a critical role in the generation of afterdischarge in the local CA1 network (Perez Velazquez & Carlen, 1999). However, it remains unknown which subtype(s) of interneurones may be responsible for such interactions and how they may actually communicate with the pyramidal cells to generate the rhythmic synchronization in the hippocampal seizure-like afterdischarge.
To elucidate the cooperative GABAergic and glutamatergic mechanism of afterdischarge generation at a network level, we analysed the interneurone subtype and functional circuit that participate in the rhythmic synchronization by recording afterdischarge responses evoked in electrophysiologically or morphologically different interneurones, as well as the neighbouring pyramidal cells, in rat hippocampal CA1-isolated slice preparations.
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Methods |
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Slice preparation
Hippocampal slices (400 µm thick) were prepared with a microslicer (DTK-1500; Dosaka EM, Kyoto, Japan) from Wistar rats (postnatal 20–30 days) which were deeply anaesthetized with diethyl ether gas and then decapitated. The CA1 region was routinely isolated from the CA3 and subiculum regions (the hippocampal CA1-isolated slice; see Fig. 1Aa), to prevent any external input from intruding through the Schaffer collateral, the perforant path, or other pathways. The stratum (s.) oriens and s. pyramidale or the s. lacunosum-moleculare (and a part of s. radiatum) of the CA1 region were lesioned with a surgical knife in some experiments. After at least 1 h of recovery, each slice was transferred to a submerged-type recording chamber continuously circulated with normal artificial cerebrospinal fluid (ACSF; 30–32°C), which consisted of (mM): 124 NaCl, 2.5 KCl, 1.2 KH2PO4, 26 NaHCO3, 1.2 MgSO4, 2.5 CaCl2 and 25 D-glucose, and was saturated with 95% O2: 5% CO2 gas (Fujiwara-Tsukamoto et al. 2003; Isomura et al. 2003a,b).
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To induce seizure-like afterdischarge, tetanic stimulation (100 Hz for 0.5 s; intensity 400 µA, duration 400 µs) was delivered through a monopolar glass stimulating electrode (0.5–1 M
, filled with 2.5 M NaCl) placed in the s. radiatum, unless otherwise stated. Whole-cell patch-clamp recordings were obtained simultaneously from two hippocampal neurones (mostly pairs of a pyramidal cell and an interneurone) in the hippocampal CA1-isolated slices under visual guidance. The membrane potentials of each neurone pair were recorded with patch-clamp amplifiers (Axopatch 1D and Axopatch 200B; Axon Instruments, Union City, CA, USA) through glass patch electrodes filled with an internal solution containing (mM): 140 potassium gluconate, 2 NaCl, 1 MgCl2, 10 Hepes, 0.2 EGTA, 2 5'-ATP Na2, 0.5 GTP Na2 and 10–15 biocytin (pH 7.4; 5–10 M) (Fujiwara-Tsukamoto et al. 2003). Electrophysiological parameters, such as firing activity and input resistance, were measured by depolarizing or hyperpolarizing current injections (± 50–500 pA, 500 ms duration; see Table 1 for details). At the end of the recordings, biocytin was loaded into the recorded neurones by repetitive current injection (+300 pA, 500 ms at 1 Hz for 15 min), followed by further incubation for 30–60 min in the ACSF. In some experiments, field potentials were recorded with the amplifier(s) through glass electrode(s) (2–5 M, filled with 2.5 M NaCl) (Isomura et al. 2002). Recorded signals were low-pass-filtered at 3–5 kHz and digitized at 5 kHz with an A/D interface (Digidata 1200, Axon Instruments).
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A mixture of DL-2-amino-5-phosphonopentanoic acid (DL-AP-5; 5 mM) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 1 mM) in saline (pH 
7.4) was injected
locally to the s. radiatum or the s. oriens/pyramidale by pressure (Picospritzer II; General Valve, Fairfield, NJ, USA; 5–10 p.s.i., 1–2 s) through a glass capillary (tip diameter, 1–2 µm). Both DL-AP-5 and CNQX were purchased from Tocris Cookson, Ballwin, MO, USA. In our preliminary experiment using a dye, the drug injection was expected to involve an area of 150–200 µm in diameter. As a control, we also confirmed that vehicle injection had no obvious effects on afterdischarge generation.
Morphological analysis. For visualizing biocytin-loaded recorded neurones, slices were fixed in 10% formalin in phosphate-buffered saline (PBS) for at least 24 h. The whole slices were immersed, without resectioning, in 0.05M Tris-HCl buffer (pH 8.0) containing 30% sucrose for 2–3 h, and slowly frozen and thawed twice. The slices were pre-treated with 0.3% H2O2 in Tris-HCl buffer for 20 min at room temperature to diminish endogenous peroxidase activity, rinsed three times in Tris-buffered saline (TBS; pH 8.0), and incubated overnight with avidin–biotin–horseradish peroxidase (HRP) complex (Vectastain Elite ABC kit; Vector, Burlingame, CA, USA; 200-fold dilution) in TBS containing 0.5% Triton X-100 at 4°C. After washes in 0.05 M Tris-HCl buffer, the slices were pre-incubated with 0.04% NiCl2 and 0.04% diaminobenzidine (DAB; Sigma, St Louis, MO, USA) in Tris-HCl buffer for 20 min, and H2O2 (final concentration, 0.003%) was added to permit peroxidase reaction for 5–15 min at room temperature. The reaction was ceased by washing the slices with Tris-HCl buffer. The slices were then embedded in Crystal/Mount (Biomeda, Foster City, CA, USA) on glass slides and coverslipped, without dehydration, for digital photography and camera lucida reconstruction under a light microscope.
Data analyses
All data in the text are expressed as the mean ±S.D., and Student's t test or ANOVA was applied for statistical comparisons.
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Results |
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As shown in our previous studies (Fujiwara-Tsukamoto et al. 2003; Isomura et al. 2003a), a strong synaptic stimulation (tetanization) induced long-lasting, GABAergic/glutamatergic rhythmic synchronization among the pyramidal cells (seizure-like afterdischarge) in mature hippocampal CA1-isolated slice preparations in normal ACSF. Field potential recordings revealed that the afterdischarge induced by the strong tetanization was synchronized broadly in the whole CA1 region, and
that the largest negative peak of oscillatory afterdischarge responses, which were much slower than population spikes, was observed in s. oriens or s. pyramidale in all of the slices examined (n= 6; data not shown), suggesting that most excitatory synaptic transmissions (and/or non-synaptic local excitations) may occur in these laminar structures during the afterdischarge. Such spatial profiles of the extracellular afterdischarge responses were always constant irrespective of the stimulating sites for induction (s. oriens or s. pyramidale; n= 4). Hereafter, the seizure-like afterdischarge was induced by tetanizing the middle portion of the s. radiatum in the CA1 region.
Seizure-like afterdischarge in different identified interneurones
To examine the network mechanism of the seizure-like afterdischarge, we recorded the changes in the membrane potential during the afterdischarge in a variety of hippocampal neurones (20 pyramidal cells and 108 interneurones) in the strata lacunosum-moleculare, radiatum, pyramidale and oriens of the CA1 region, in combination with the neighbouring pyramidal cells in s. pyramidale (Fig. 1Aa). Of the 108 interneurones recorded, 64 well-visualized ones were morphologically identified as lacunosum-moleculare (LM) cells (n= 12), bistratified cells (n= 4), basket/chandelier (axo-axonic) cells (n= 11), oriens-lacunosum-moleculare (O-LM) cells (n= 2), and other subtypes of cells (n= 35) (Sik et al. 1995; Freund & Buzsáki, 1996). The last group (other subtypes) of cells includes trilaminar cells as well as various ‘monolaminar’ and ‘bilaminar’ cells, which have not been classified further by the conventional morphological definition (Parra et al. 1998).
In a typical pyramidal cell, zero, one, or two action potentials synchronous with those in another pyramidal cell were elicited in each oscillatory depolarizing response during the seizure-like afterdischarge (Fig. 1Ab–d), as previously reported (Fujiwara-Tsukamoto et al. 2003). The generation of action potentials was greatly depressed during large post-tetanic depolarization prior to the appearance of afterdischarge in the pyramidal cells, probably owing to a strong GABAA-mediated depolarizing inhibition (i.e. shunting effect; see Alger & Nicoll, 1979) which lasted for several seconds after the tetanization (Fig. 1Ad). The interneurone illustrated in Fig. 1B is an LM cell which was located horizontally around the border between s. lacunosum-moleculare and s. radiatum (Fig. 1Ba; Chapman & Lacaille, 1999). This LM neurone, which had the properties of a non-fast-spiking (non-FS) neurone (Fig. 1Bb and c), exhibited no, or only small, oscillatory responses without spiking during the afterdischarge (Fig. 1Bd). Six of 12 LM cells never discharged and the others displayed only a small number of action potentials while the afterdischarge was expressed in the pyramidal cells.
The two interneurones illustrated in Fig. 2 are a bistratified cell and a putative chandelier cell with fast-spiking (FS) properties (Fig. 2Ab and c, and Bb and c), both of which were located around the border between s. oriens and s. pyramidale (Fig. 2Aa and Ba). The bistratified cell spread its axon broadly into s. radiatum and s. oriens, but not into s. pyramidale (see Buhl et al. 1996), while the extension of the chandelier cell axon was restricted to the border between s. pyramidale and s. oriens (Buhl et al. 1994b). These interneurones exhibited robust bursting responses (3–8 action potentials) during the afterdischarge, which were synchronous with oscillatory responses in the simultaneously recorded pyramidal cells (Fig. 2Ad and Bd). The first discharge of their burst responses frequently preceded the onset of the oscillatory response in the pyramidal cells. These interneurones also discharged at a very high frequency during the preceding post-tetanic depolarization, unlike the pyramidal cells. Three of four bistratified cells and 7 of 11 basket/chandelier cells displayed an outstanding generation of burst spikes during the afterdischarge.
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The results obtained from our dual whole-cell patch-clamp recordings suggest that afterdischarge responses in the hippocampal interneurones may be dependent on their intrinsic firing ability as well as on their somatic location in the CA1 region. Therefore, the 108 recorded interneurones were classified into six distinct groups according to their electrophysiological properties and somatic locations (Table 1; FS interneurones in s. pyramidale (FS (s.p.), n= 5) and s. oriens (FS (s.o.), n= 15); non-FS interneurones in s. lacunosum-moleculare (non-FS (s.l.m.), n= 21), s. radiatum (non-FS (s.r.), n= 25), s. pyramidale (non-FS (s.p.), n= 12), and s. oriens (non-FS (s.o.), n= 30)). Besides these classified cells, only one FS interneurone was found in the s. radiatum in the present experiments (data not shown). We defined the FS and non-FS cells using the criterion of whether or not the mean discharge rate was higher than 100 Hz per 0.5 nA current (see Table 1). The amplitudes of after-hyperpolarization (AHP) in all the interneurone groups were significantly larger than those in the pyramidal cells, and also, the FS interneurone groups displayed less spike adaptation (accommodation) and shorter spike width than the non-FS interneurone groups and the pyramidal cells (Table 1), suggesting that the criterion used here was valid.
Given that oscillatory afterdischarge responses in the pyramidal cells are driven by excitatory GABAergic inputs, their presynaptic GABAergic interneurones should generate action potentials synchronously. In fact, action potentials in most of the recorded interneurones were synchronous with oscillatory responses in the pyramidal cells during the afterdischarge. However, the mean discharge number per oscillatory response (or the oscillation cycle in the afterdischarge) was very different among the six interneurone groups (Fig. 4A; (in spikes cycle–1) non-FS (s.l.m.) interneurones, 0.21 ± 0.38; non-FS (s.r.), 0.58 ± 0.63; non-FS (s.p.), 2.25 ± 2.13; FS (s.p.), 3.70 ± 2.26; non-FS (s.o.), 1.68 ± 1.26; FS (s.o.), 4.20 ± 2.71; one-way ANOVA, P < 0.001). The non-FS (s.l.m.) interneurone group generated much fewer action potentials during the afterdischarge than all of the non-FS (s.p.), non-FS (s.o.), FS (s.p.), and FS (s.o.) interneurone groups (Duncan's multiple range test, at most P < 0.01). The non-FS (s.r.) interneurone group also generated fewer action potentials than all of these groups (P < 0.01).
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Furthermore, we analysed the temporal firing patterns during the afterdischarge in these interneurone groups. As shown in Fig. 5A, the discharge timings in most of the active interneurones were precisely time-locked to those in the simultaneously recorded pyramidal cells. This analysis again indicates that the FS and non-FS interneurones in s. pyramidale and oriens discharged more frequently than the non-FS interneurones in s. lacunosum-moleculare and s. radiatum. In particular, the first action potentials of oscillatory bursting responses in many of the FS interneurones (10 of 14 cells) tended to precede the first discharges in the simultaneously recorded pyramidal cells (Fig. 5B; paired t test, n= 14, P < 0.001; see also Fig. 2). This suggests that these interneurones are unlikely to inhibit the activity of their postsynaptic pyramidal cells during the afterdischarge. It should be emphasized here that we didn't find any ‘anti-phasic’ interneurones, which would discharge only in the resting periods of afterdischarge responses evoked in the pyramidal cells. In addition, we found no ‘pace-maker’-like interneurones with an intrinsically rhythmic bursting property in the CA1 region.
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Next, we confirmed the synaptic communication between the pyramidal cells and the interneurones in s. oriens/pyramidale during the seizure-like afterdischarge, since both GABAergic and glutamatergic synaptic transmissions are necessary for afterdischarge generation in hippocampal CA1-isolated slice preparations (Fujiwara-Tsukamoto et al. 2003). Thirteen of the 108 interneurones recorded had direct synaptic connections with the simultaneously recorded pyramidal cells (11 interneurone-to-pyramidal cell and 2 pyramidal cell-to-interneurone pairs, consisting of 2 interneurones in s. lacunosum-moleculare, 6 in s. radiatum, 3 in s. pyramidale, and 2 in s. oriens). Consistent with a previous study (Knowles & Schwartzkroin, 1981a), we failed to record any direct excitatory synaptic responses between the CA1 pyramidal cells. Figure 7A illustrates a presynaptic putative basket cell and postsynaptic pyramidal cell pair. This basket cell densely innervated the pyramidal cell at its somatic site in the s. pyramidale in a restricted manner (Fig. 7Aa), and the unitary inhibitory postsynaptic potentials (uIPSPs) were evoked in the postsynaptic pyramidal cell by the spiking of the basket cell in a normal resting condition (Fig. 7Ab and c; see Buhl et al. 1996). These two neurones discharged synchronously during the afterdischarge (Fig. 7Ad), and once the tetanic stimulation was applied, the evoked unitary responses in the pyramidal cell were transiently converted from hyperpolarizing to depolarizing ones (Fig. 7Ad, lower panel; see also Fujiwara-Tsukamoto et al. 2003). Thus, it is most likely that the interneurones might activate the pyramidal cells, probably by means of excitatory GABAergic synaptic transmissions, within s. oriens/pyramidale during the afterdischarge. In contrast, a presynaptic interneurone located in the boundary between s. radiatum and lacunosum-moleculare always evoked clear uIPSPs in a postsynaptic pyramidal cell even during the constant expression of afterdischarge (Fig. 7B). On the other hand, Fig. 7C illustrates unitary excitatory postsynaptic potentials (uEPSPs) in a postsynaptic interneurone in s. oriens, which were evoked by a presynaptic pyramidal cell (Fig. 7Ca and b). These two neurones also discharged synchronously during the afterdischarge, although the spiking activity in the interneurone was more prominent than that in the pyramidal cell (Fig. 7Cc).
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The afterdischarge-related synaptic interactions in s. oriens and s. pyramidale imply that a neural circuit for synchronization of afterdischarge activity may exist within these laminar structures. Therefore, we examined whether microsurgical lesions in s. oriens/pyramidale may result in some perturbation in neuronal synchronization. As shown in Fig. 9, synchronized field responses of the afterdischarge were normally recorded in two different sites of intact CA1 slices (Fig. 9A and E; n= 7) and CA1 slices with the s. lacunosum-moleculare lesioned (Fig. 9B and E; n= 6). In contrast, the field responses of the afterdischarge were completely ‘desynchronized’ between two recording sites in CA1 slices with the s. oriens/pyramidale lesioned (Fig. 9C and E; n= 6).
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Finally, the afterdischarge was found to be inducible in the CA1 region even in the ‘s.r.-lesioned mini-slices’ consisting of s. oriens/pyramidale and the adjacent perisomatic part of s. radiatum (Fig. 9F; duration 15.6 ± 3.2 s, n= 5), although the duration of afterdischarge responses was relatively shortened in some slices probably because of a considerable loss of living pyramidal cells. These results suggest that the interneurones in s. lacunosum-moleculare and at least the distal dendritic part of s. radiatum may basically be dispensable for the afterdischarge generation, and that the distal portions of the apical dendrites of the pyramidal cells may not participate in the GABA/glutamate-dependent generation of afterdischarge activity. Thus, the neuronal interactions within s. oriens/pyramidale are likely to be most critical for synchronization, maintenance, and, perhaps, rhythm generation of the seizure-like afterdischarge activity in the CA1 region.
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Discussion |
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Based on these results, we propose a hypothetical model for local afterdischarge generation (Fig. 10). In our model, the pyramidal cells and interneurones are strongly excited during tetanization, which causes extracellular K+ accumulation to stimulate neighbouring neurones synergistically (Kaila et al. 1997; Smirnov et al. 1999). The excited interneurones activate GABAA receptors in the pyramidal cells, leading to massive Cl– influx and HCO3– efflux (Isomura et al. 2003b). Then, Cl– accumulation and subsequent HCO3– redistribution in the pyramidal cells make their GABAA reversal potentials much higher than their resting membrane potentials (Staley et al. 1995; Staley & Proctor, 1999). Consequently, the post-tetanic depolarization, often carrying gamma oscillations (Whittington et al. 1997; Bracci et al. 1999), and subsequent afterdischarge are expressed in the local network. There are only a few direct recurrent connections among the CA1 pyramidal cells (Knowles & Schwartzkroin, 1981a; Amaral & Witter, 1995), but their recurrent collaterals innervate many interneurones in s. oriens/pyramidale (Knowles & Schwartzkroin, 1981a; Lacaille et al. 1987; Freund & Buzsáki, 1996). Accordingly, it is conceivable that local GABAergic interneurones in s. oriens/pyramidale synchronously excite the glutamatergic pyramidal cells, which, in turn, activate the interneurones of origin. Thus, these neurones may form a layer-specific ‘positive feedback circuit’ to express the afterdischarge. The locally generated afterdischarge activity will propagate into other regions where GABAergic excitation no longer occurs (Isomura et al. 2003a).
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The candidates for local interneurones participating in the neuronal synchronization are likely to include the basket, chandelier, bistratified and trilaminar cells (see Figs 2, 3, 6 and 7; see also Sik et al. 1995; Freund & Buzsáki, 1996). In fact, these interneurones are directly connected with the pyramidal cells in a reciprocal fashion (Buhl et al. 1994a; Halasy et al. 1996; Ali & Thomson, 1998; Ali et al. 1998; Maccaferri et al. 2000; Pawelzik et al. 2002). In particular, parvalbumin-positive hippocampal interneurones, most of which are basket cells with FS properties, are concentrated in the s. oriens/pyramidale (Kawaguchi et al. 1987; Pawelzik et al. 2002), and they receive excitatory synaptic input much more intensely than other types of interneurones (Gulyás et al. 1999). Although the mechanism of ‘synchrony’ in the afterdischarge can be accounted for by a cooperative action of these interneurones and the pyramidal cells, the mechanism of its ‘rhythmicity’ still remains a mystery in our network model. It seems unlikely that intrinsic membrane potential oscillations in the LM interneurones (Chapman & Lacaille, 1999) or slow GABAA transmission by these LM interneurones (Banks et al. 2000; cf. Bertrand & Lacaille, 2001) may contribute to rhythm generation in the seizure-like afterdischarge, because the present results have clearly demonstrated that most LM interneurones are not so active during the afterdischarge (see Figs 1 and 6). The data obtained from our lesion experiments imply that a rhythm generator probably exists in s. oriens/pyramidale, but not in s. lacunosum-moleculare. Although we cannot as yet exclude the possibility that interneurones in s. lacunosum-moleculare/radiatum may partly contribute to the synchrony of the afterdischarge, they appear to be just ‘slaves’ following other active neurones, and not to be essential for the rhythm generation. It is also unlikely that a rebound depolarization following strong IPSP may drive the next oscillatory cycle in the pyramidal cells (cf. Cobb et al. 1995), because such strong IPSPs were not observed in the pyramidal cells recorded during the afterdischarge. Hence, it should be hypothesized that intrinsic membrane potential oscillations in a population of pyramidal cells (Leung & Yim, 1991) or unidentified interneurones underlie the rhythm generation of the afterdischarge.
The synchronization mechanism of the tetanus-induced seizure-like afterdischarge might be partly similar to that of seizure-like afterdischarge induced in a low Mg2+ condition, in that depolarizing GABAergic responses appear to contribute to the generation of low Mg2+-induced epileptiform activity (Köhling et al. 2000; Perez Velazquez, 2003). In contrast, these synchronizing events of seizure-like afterdischarge are apparently different from that of disinihibition-dependent afterdischarge which is produced by application of GABAA antagonists such as bicuculline and picrotoxin (Borck & Jefferys, 1999). The direct glutamatergic recurrent connections among the pyramidal cells dominantly contribute to the epileptogenesis in a bicuculline-induced disinhibitory condition (Crépel et al. 1997), as well as in a collateral-sprouting condition after chronic kainate treatment (Smith & Dudek, 2001, 2002). The tetanus-induced seizure-like afterdischarge is also different from hippocampal theta oscillations in that GABA naturally acts as an inhibitory (hyperpolarizing) mediator; the basket and chandelier cells discharge at the interval of pyramidal cell firing, whereas the bistratified and O-LM cells discharge synchronously with the pyramidal cells during the theta oscillations (Ylinen et al. 1995; Klausberger et al. 2003, 2004). It remains unknown, however, what functional roles the bistratified and O-LM cells might play in the generation of seizure-like afterdischarge. Taken together, there would be several different mechanisms underlying the rhythmic synchronizations such as seizure-like activities and theta oscillations in the same (CA1) region of the hippocampus, and distinct types of GABAergic interneurones might play a key role in controlling these synchronous oscillatory phenomena.
Our ‘positive feedback circuit’ hypothesis for the rhythmic synchronization may be practically useful to understand the seizure activity in human temporal lobe epilepsy. It has long been believed that reduced GABAergic inhibition (disinhibition) would lead to the hyperexcitability of glutamatergic neurones in the cerebral cortex of epilepsy patients. However, GABAergic interneurones and their terminals containing glutamate decarboxylase are still preserved in the human epileptic hippocampus (Babb et al. 1989), and GABA, as well as glutamate, is massively released in the hippocampus during spontaneous seizures of temporal lobe epilepsy (During & Spencer, 1993). Although an abnormal loss of GABA transporters could decrease non-synaptic GABA release by ‘GABA transporter reversal’ (During et al. 1995), hippocampal GABA transporters are also preserved in temporal lobe epilepsy patients (Mathern et al. 1999). It has recently been reported that non-pyramidal interneurones are indeed alive and functional in epileptic tissues of the human temporal cortex (Menendez de la Prida et al. 2002). Furthermore, Cohen et al. (2002) have shown that interictal epileptic activity is mediated by depolarizing GABAergic transmission, in cooperation with glutamatergic transmission, in hippocampal (subicular) slices obtained from temporal lobe epilepsy patients. Thus, a decrease in GABAergic interneurones that has so far been considered to occur in epilepsy cases (e.g. DeFelipe, 1999) may not result in high excitability of the hippocampal or cortical pyramidal cells, but rather, an anomalous conversion of GABA action from inhibition to excitation may sometimes positively contribute to the local generation of ictal or interictal activity. It is therefore possible that such layer-specific positive feedback interactions between pyramidal cells and interneurones might causally be involved in the expression of seizure activity in human temporal lobe epilepsy.
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Footnotes |
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T= 0 ms) in a simultaneously recorded pyramidal cell as a standard neurone during the afterdischarge (8–20 s). Upward columns indicate the probabilities of the first (black) and total (grey) action potentials in relation to the oscillatory responses in test neurones (pyramidal cells or interneurones), and downward black columns indicate those of the first action potentials in relation to the oscillatory responses in the standard pyramidal cells. The discharges in most of the interneurones examined were time-locked to those in the simultaneously recorded pyramidal cells; the interneurones in the s. pyramidale and s. oriens particularly exhibited robust spiking during the afterdischarge. B, upper panels, superimposed traces of the first action potentials in a non-FS (s.r.; left) and an FS (s.p.; right) interneurone, aligned with the onset of the first action potentials in standard pyramidal cells (PC) (dotted lines) during the afterdischarge. Lower panel, temporal changes in relative discharge timing of the non-FS (
) and FS (•) interneurones to the pyramidal cells in the time course of afterdischarge.
