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1Université Pierre et Marie Curie, and Centre National de la Recherche Scientifique, Paris, France; 2School of Biosciences, Cardiff University, Cardiff, United Kingdom; and 3Deparmento de Bioquímica, Bromatología, Toxicología y Medicina Legal, Facultad de Farmacia, Sevilla, Spain4
Submitted 3 July 2006; accepted in final form 7 September 2006
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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; Crunelli and Leresche 2002). Human investigations have indicated an underlying multi-factorial genetic background and the presence of molecular genetic changes in GABAA receptors (GABAARs) (Gardiner 2005; Noebels 2003). In particular, linkage analysis in an IGE cohort with only typical absence indicated regions coding for GABAA 
5 and 
3 subunits as susceptibility loci (Lu et al. 2002, 2004). On the other hand, mutations in the 
2 or 
subunits have been detected in IGE probands with a phenotype more complex than pure absence (Baulac et al. 2001; Harkin et al. 2002; Kananura et al. 2002; Marini et al. 2003; Wallace et al. 2001). The proteins of these mutant genes have been shown to give rise to a decreased GABAAR function via different mechanisms and not in every expression system (Bianchi et al. 2002; Bowser et al. 2002; Dibbens et al. 2004; Harkin et al. 2002; Kang and Macdonald 2004).
A decreased GABAAR function has also been suggested on the basis of experimental studies. Thus although no apparent change in the GABAAR system had been found in the feline penicillin model (Gloor and Fariello 1988), indirect evidence indicating of a reduced GABAAR function was later reported in the neocortex of two inbred models, genetic absence epilepsy rats from Strasbourg (GAERS) (Spreafico et al. 1993) and Wistar albino Glaxo/Rij (WAG/Rij) rats (D’Antuono et al. 2006; Luhmann et al. 1995). GABAARs in the thalamus have also been implicated in the pathophysiology of typical absence seizures because GABAA antagonists in vitro have been shown to transform spindle-like activity into paroxysmal discharges resembling SWDs (Sohal et al. 2003; von Krosigk et al. 1993). Furthermore, direct evidence of a role for GABAARs in the nucleus reticularis thalami (NRT), one of the main intrathalamic GABAergic source, has come from the hypersynchroneous 3-Hz firing observed in the isolated thalamic network of GABAA 3 subunit knockout mice, the phenotype of which includes SWDs (Huntsmann et al. 1999). Indeed, in line with this evidence, a decreased synchronization follows the selective enhancement of intra-NRT inhibition by clonazepam (Sohal and Huguenard 2003).
Notwithstanding all these human and experimental data, however, the full spectrum of the genetic defects underlying typical absence seizures has only been partially elucidated, the expression and functional profiles of putative abnormal protein(s) within the thalamocortical network are undefined, and the pathophysiological mechanism(s) by which these proteins would lead to absence paroxysms are poorly understood. Here we have carried out a systematic functional analysis of GABAARs in preseizure GAERS, a well-established genetic model of typical absence seizures, which lacks additional neurological and neuropathological abnormalities. We report that differences in GABAA IPSCs, and their modulation by GABAB receptors, between preseizure GAERS and age-matched non-epileptic control (NEC) rats, exist in the NRT but not in upper somatosensory cortical layers or ventrobasal thalamus (VB).
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Slices were prepared from young male and female GAERS and NEC rats (range: 12–16 day old). After decapitation the brain was removed, and a block containing either the somatosensory cortex or the thalamus was dissected. Coronal cortical slices or horizontal thalamic slices containing the NRT, the ventral posterolateral and ventral posteromedial nuclei were prepared in ice-cold saline using a vibroslice (HV650V, Microm) (Le Feuvre et al. 1997). Slices, 220 µm thick, were kept at 32°C in oxygenated saline (95% O2-5% CO2) before being transferred, one at the time, to the experimental setup, where they were maintained at room temperature (20–22°C) and perfused at a rate of 1–2 ml/min with an oxygenated medium of composition (in mM) 125 NaCl, 2.5 KCl, 2 CaCl2, 1 MgCl2, 1.25 NaH2PO4, 26 NaHCO3, and 25 glucose, pH 7.3, osmolarity: 305 mosM.
Membrane currents were recorded from the soma of cortical and thalamic neurons visualized under Nomarski optics. Recording pipettes were pulled from borosilicate glass using a Narishige micropipette puller, and coated with wax. Electrodes were filled with the following solution (in mM): 115 CsCl, 1 CaCl2, 5 MgCl2, 10 EGTA, 10 HEPES, and 4 Na-ATP (pH 7.3, osmolarity 300 mosM; electrode resistance: 1.5–3 M
). Biocytin (
2 mg/ml) was added to the internal solution to assess the position and morphology of the recorded neurons (see Immunohistochemistry). Once a high-resistance seal had been established, the holding potential was set to –60 mV and the whole cell, voltage-clamp configuration was obtained. Values of access resistance ranged from 4–6 M at the beginning of the recording to 4–8 M at the end. At least 70% of these values were compensated. Patch-clamp electrodes were connected to an Axopatch 200B amplifier (Molecular Devices). Voltage protocols and acquisition were controlled by Axograph 4.9 (Molecular Devices). The membrane currents were filtered by a 4-pole Bessel filter set at a corner frequency of 2 kHz, digitized on-line at a sampling rate of 10 kHz and later analyzed using Axograph 4.9. Data were not collected until 
10 min after patch rupture to allow the internal and external solutions to equilibrate.
Isolation of GABAA IPSCs was obtained by adding the ionotropic glutamate receptor antagonists, D-APV (50 µM) and 6-cyano-7-nitroquinoxalene-2,3-dione (CNQX, 10 µM) to the perfusion medium. Evoked IPSCs (eIPSCs) were elicited from a holding potential of –60 mV by extracellular electrical stimulation, using a glass pipette (6–8 µm tip diam) filled with the extracellular medium. The stimulating electrode was positioned 25–60 µm from the recorded neuron. Square pulses of 20-µs duration were applied at a frequency of 0.05 Hz, and the stimulation strength (10–40 V) was adjusted as to obtain an eIPSC amplitude of 1.5 times the threshold response.
Analysis of mIPSCs
Miniature IPSCs (mIPSCs) were detected and analyzed using AxoGraph 4.9 program. The detection threshold was set as 4 time the r.m.s. baseline noise. All automatically detected events were individually checked, and the decay time constant was measured on events which were judged to be single mIPSCs. After sorting, depending on the brain area, between 15 and 30% of the collected mIPSCs were kept for the kinetic analysis. The criteria were the presence of a smooth decay phase with no overlapping events and a minimum of 50 mIPSCs was required for a given neuron to be included in the database. The time course of decay of the mIPSCs was analyzed on average events obtained by aligning individual mIPSCs by their rising phases. All the other parameters (10–90% rise time and amplitude) were measured on individual mIPSCs and then averaged. Decay kinetics was determined by fitting the falling phase of the average mIPSCs with a single- or a double-exponential function (with 
1 and 2 representing the 1st and 2nd decay time constant, respectively). When a double-exponential function was needed, a weighted decay time constant (weighted ) derived from these fitted curves was calculated to allow a simple quantification of the mIPSCs duration (Huntsman and Huguenard 2000).
Quantitative data in the text and figures are given as means ± SE, and the statistical significance was tested using Student’s t-test. Differences in mIPSCs frequency, amplitude and kinetics cumulative distributions were determined using the Kolmogorov-Smirnov test (KS).
Drugs
(±) Baclofen, CGP 55845A, and CGP 35348 containing solutions were prepared immediately before the experiment. All chemicals, except CGP 55845A and CGP 35348, were purchased from Sigma (France), Latoxan (France) and ICN (France). All drugs were bath applied.
Immunohistochemistry
Slices were fixed overnight in 0.1M phosphate-buffered saline (PBS, pH 7.4) containing 4% paraformaldehyde, washed with 0.1% PBS and then incubated with gelatin triton 0.25% in 0.1M PBS for 30 min. Biocytin-filled neurons were revealed after incubation with streptavidin Alexafluor 568 antibody (1:500 dilution, Molecular Probes, Eugene, OR) in 0.1M PBS for 4h. After washes in 0.1 M PBS, slices were mounted on vectashield (Vector Labs, Burlingame, CA) for fluorescent microscope examination. The position of labeled neurons was confirmed using the Paxinos and Watson atlas (Paxinos and Watson 1998). Cortical cells were classified as pyramidal neurons on the basis of their typical pyramidal shape and the presence of clearly distinguishable apical and basal dendritic trees. The remaining cells were classified as nonpyramidal neurons.
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RESULTS |
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In the presence of glutamatergic receptor antagonists and TTX, at a holding potential of –60 mV, inward spontaneous GABAAR mIPSCs were recorded in all somatosensory cortical, VB and NRT neurons under investigation. The properties of these mIPSCs are summarized in Table 1.
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), we restricted our analysis to these cortical layers and recorded 20 pyramidal and 20 nonpyramidal neurons in both, age-matched, GAERS and NEC. The mIPSCs recorded from these pyramidal and nonpyramidal neurons had similar rise time, amplitude, and decay time constant (Fig. 1; Table 1). More importantly no difference was observed for these parameters between GAERS and NEC (Fig. 1). We did, however, observed a lower mIPSC frequency in pyramidal neurons of GAERS compared with NEC (Table 1).
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1, 2, and weighted of mIPSCs in the NRT were significantly smaller (44, 40, and 40%, respectively) in GAERS compared with NEC (Table 1). To examine whether the different decay kinetics observed for averaged mIPSCs was not due to the occurrence of some peculiarly fast decaying mIPSCs in GAERS NRT neurons, we fitted individual mIPSC decays with a single-exponential function. As illustrated in Fig. 3C, the distribution of the decay time constants of individual mIPSCs was significantly different between GAERS and NEC NRT neurons (n = 259 and 185 mIPSCs, respectively, P < 0.05 Kolmogorov-Smirnov test). Similarly, the amplitude distribution of individual mIPSCs was significantly different between GAERS and NEC (P < 0.05 Kolmogorov-Smirnov test; Fig. 3D). No differences in passive membrane properties (measured on responses to a –10-mV step) were observed between GAERS (n = 14) and NEC (n = 10) NRT neurons (input resistance: 285 ± 34 and 252 ± 21 M; 1: 0.46 ± 0.04 and 0.5 ± 0.06 ms; 2: 3.72 ± 0.26 and 4.23 ± 0.33 ms, respectively; all P > 0.2).
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To investigate potential differences in the presynaptic control of GABA release through GABAB receptors, we tested the effect of baclofen on the mIPSCs recorded in the three areas of interest. Similar to the results obtained when analyzing the basic mIPSCs properties, differences in the presynaptic GABAB control were specific for mIPSCs recorded in NRT neurons. Thus although 1–10 µM (±)baclofen reversibly decreased the frequency of the GABAA mIPSCs in all NRT neurons tested, a clear difference in the magnitude of the effect was observed between NEC and GAERS (Fig. 4A1). In NEC NRT neurons, applications of 1, 3 and 10 µM baclofen decreased by 38 ± 1, 56 ± 2 and 59 ± 2% (n = 6 for each concentration), respectively, the mIPSC frequency, whereas these concentrations only induced a 12 ± 3 (n = 8), 37 ± 3 (n = 6), and 44 ± 3% (n = 6) decrease in GAERS (P < 0.0001, P < 0.0005, and P < 0.005 for 1, 3, and 10 µM, respectively). Thus the baclofen ED50 was 1.6 and 0.8 µM in GAERS and NEC, respectively, and its maximal efficacy was 25% lower in GAERS compared with NEC (Fig. 4A3). Also note that the small effect detected at 0.3 µM baclofen was similar in GAERS and NEC. In either strains, the baclofen effect on mIPSC frequency was not associated with changes in the amplitude distribution (Fig. 4A2), and was antagonized by the specific GABAB receptor antagonist CGP55845A (100 nM; Fig. 4A1).
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Evoked GABAA IPSCs in GAERS and NEC thalamus
We then examined the properties of pharmacologically isolated eIPSCs in NRT and VB neurons of the two strains. The decay of the eIPSC in NRT neurons of GAERS was faster than in NEC (Fig. 5A), and as for the mIPSCs 1, 2, and weighted were significantly smaller (47, 42, and 46%, respectively) in GAERS than in NEC (Table 1). In contrast, no differences in the properties of the eIPSCs were observed between GAERS and NEC VB TC neurons (Fig. 5D; Table 1).
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), we used this stimulation protocol to investigate the strength of evoked inhibition at both NRT-NRT and NRT-TC synapses. Two eIPSCs separated by 140 or 400 ms were elicited in NRT neurons, with the 140-ms interval being the period between successive spike-and-wave complexes during SWDs in GAERS (Slaght et al. 2002). As expected, paired-pulse depression occurred in NRT neurons and was significantly smaller (46 and 29% for 140- and 400-ms intervals, respectively) in GAERS than in NEC (Fig. 5, B and C, black traces). The mean amplitude decrease was 53 ± 4% in NEC versus 29 ± 5% in GAERS (n = 10 for both, P < 0.002) and 49 ± 4% in NEC versus 35 ± 3% in GAERS (n = 10 and 12, P < 0.05) for 140- and 400-ms intervals, respectively. In contrast, in VB TC neurons the paired-pulse depression tested at 140ms interval was identical in NEC (51 ± 5%, n = 5) and in GAERS, (43 ± 3%, n = 7; P = 0.13; Fig. 5D, black traces). Application of CGP55845A (100 nM) or CGP35348 (1 mM), however, failed to antagonize the paired-pulse depression in NRT neurons (NEC: 45 ± 5%, n = 8; GAERS: 29 ± 4%, n = 5 for 140-ms interval; NEC: 40 ± 6%, n = 9; GAERS: 31 ± 7%, n = 6 for 400-ms interval) (Fig. 5, B and C, gray traces), indicating that the mechanism involved in this type of synaptic depression does not involve GABAB autoreceptors in both strains. A similar lack of effect of CGP55845A (100 nM) was observed in the paired-pulse depression of IPSCs recorded in VB TC neurons (Fig. 5D, gray traces). |
DISCUSSION |
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mIPSCs properties
The properties (kinetics and amplitude) of mIPSCs recorded in NEC cortical neurons are similar to those reported previously by others (Defazio and Hablitz 1998; Xiang et al. 1998; Zhou and Hablitz 1997), and no difference was observed between GAERS and NEC in cortical layer II/III pyramidal and nonpyramidal neurons. However, because our sample did not cover all cortical layers and their neuronal types, we cannot fully exclude the possibility of an altered GABAAR function in the GAERS cortex. Indeed, a decreased peak conductance of the fast (GABAA) IPSP has been described in deep layer pyramidal neurons of adult WAG/Rij rats (D’Antuono et al. 2006). Nevertheless, our results do not support the Luhmann and al. (1995) suggestion of decreased GABAAergic inhibition in layers II/III pyramidal neurons in WAG/Rij rats. However, because these authors did not isolate the different components of the complex synaptic response under investigation, their results could also reflect changes in glutamatergic transmission. Moreover, whereas our results were in preseizures GAERS, Luhman et al. (1995) studied adult WAG/Rij (i.e., rats that have had seizures for several months), raising the possibility that their findings could be a consequence of the seizures. Both the slow decay of mIPSCs in NEC NRT neurons and the difference in decay time constant between NEC NRT and VB mIPSCs are consistent with previous reports of sIPSCs recorded in normal Sprague-Dawley rats (Browne et al. 2001; Huntsman and Huguenard 2000; Zhang et al. 1997) and mice (Huntsman et al. 1999). In contrast, mIPSCs with a fast decay kinetics as those observed here for the GAERS have never been reported in the NRT of nonepileptic control animals. Previous work has suggested that the differences in mIPSC kinetics between VB and NRT could be related to the different ratio of 1 to 3 subunits in the two nuclei (Browne et al. 2001). Interestingly, a recent study has shown that NRT neurons with faster spontaneous IPSCs have a higher probability to express the 1 subunit (Huntsman and Huguenard 2006). Furthermore, evidence from expression systems also point to 2L and 2S in defining the kinetics of GABAergic currents (Benkwitz et al. 2004; Haas and Macdonald 1999; Lagrange and Macdonald 2005). Notwithstanding the fact that mIPSC properties are generally considered to be tightly linked to subunit composition, other parameters such as receptor density, subcellular localization, occupancy and phosphorilation could also influence mIPSC characteristics (Auger and Marty 2000). Finally, it is unclear at present why a recent QTL analysis on GAERS and first and second generation offsprings of GAERS x Brown Norway rats did not highlight any susceptibility loci in regions coding for any of the GABAAR subunits (Rudolf et al. 2004), although this type of analysis cannot be considered comprehensive.
It is also interesting to note that subtle kinetics differences in GABAA mIPSCs were reported in perirhinal cortical neurons in seizure-prone compared with seizure-resistant rats (McIntyre et al. 2002). In this model of temporal lobe epilepsy, as in the present data, these changes were present prior to seizure onset, suggesting that alterations in the fine tuning of GABAAergic phasic inhibition may be of epileptogenic significance both in convulsive and nonconvulsive epileptic seizures.
Modulation of GABAA IPSCs by GABAB autoreceptors
In NEC, baclofen produced a decrease in NRT and VB mIPSC frequency similar to that previously described in other nonepileptic rodents (Le Feuvre et al. 1997; Ulrich and Huguenard 1996). However, in the GAERS NRT, but not in VB, there was a decreased sensitivity of GABAB autoreceptors to baclofen. It is difficult at present to relate the differences in the action of baclofen on the frequency of mIPSCs between NRT-NRT and NRT-VB synapses in the two strains to a particular cellular/molecular abnormality. In fact, there is no difference in the various GABABR1 isoforms between GAERS and NEC in both VB and NRT (Holter et al. 2005), although their sampling protocol pooled together GABAB auto-, hetero-, and postsynaptic-receptors in the VB, and auto- and hetero-receptors in the NRT. Alternatively, the observed differences in the baclofen action between GAERS and NEC may be related to GABABR1 transduction mechanisms and/or alterations in GABABR2 expression and function in the two thalamic areas, which have so far not been investigated.
The kinetics of the NEC eIPSCs was similar to that previously reported for eIPSCs in the NRT of nonepileptic control rats (Huntsman and Huguenard 2000; Zhang et al. 1997) and mice (Huntsman et al. 1999). The faster eIPSC decay of GAERS mirrors the fast mIPSC decay kinetics, indicating that its underlying mechanism is not affected by synchronous multi-vesicular release. More importantly, the GAERS eIPSCs showed a 45% smaller paired-pulse inhibition than the NEC IPSCs that would undoubtedly play a major role in allowing the expression of the strong LTCP-mediated bursts of action potentials that are present in GAERS NRT neurons during SWDs in vivo (Slaght et al. 2002).
In contrast to a previous report in Sprague Dawley rats (Ulrich and Huguenard 1996), the paired-pulse depression of both GAERS and NEC IPSCs was insensitive to GABAB antagonists, suggesting that it is not mediated by GABAB receptors. In other structures, such as the hippocampus, analysis of GABAB autoreceptor-dependent paired-pulse depression has also resulted in conflicting results (Davies et al. 1991; Jensen et al. 1999; Lambert and Wilson 1994; Mott et al. 1993; Otis and Mody 1992; Poncer et al. 2000; Vigot et al. 2006), indicating that the ability to activate these presynaptic receptors may be highly dependent on the type of preparation and stimulation protocols. Alternatively, other presynaptic mechanisms/receptors may be controlling intra-NRT GABA release.
Significance of intra-NRT inhibition properties for network excitability
Changes in intra-NRT inhibition are known to drastically affect thalamic oscillations. Full pharmacological block of NRT GABAARs or knockout of the 3 subunit leads to highly synchronized, paroxysm-like discharges in vitro (Blumenfeld and McCormick 2000; Huguenard and Prince 1994; Huntsman et al. 1999; von Krosigk et al. 1993). These, however, are marked pharmacological and genetic manipulations that lead to the total disappearance of intra-NRT inhibition. Although we did not directly compare the excitability of isolated GAERS and NEC NRT network in vitro, preliminary computational analysis (unpublished observations) using an NRT network model (Toth and Crunelli 2006) indicates that the GABAA IPSC features of GAERS consistently gives rise to an increased excitability to both random and periodic stimuli that includes, among other effects, a resonance output within the frequency range of the SWDs observed in vivo in GAERS (Slaght et al. 2002).
In summary, the present data indicate that one important epileptogenic component of typical SWDs may be related to subtle alterations in the kinetics and paired-pulse depression of phasic GABAAR-mediated inhibition specifically in the NRT and not to a full loss-of-function of GABAARs that globally involves cortical and other thalamic nuclei. In this respect, our data in a genetic model of typical absence seizures are in line with the subtle abnormalities in GABAAR function resulting from human mutations in genetically simpler IGEs (Bianchi et al. 2002; Bowser et al. 2002) and suggest caution in extrapolating to the human condition the significance of results obtained in the presence of a total GABAAR synaptic block. The pathophysiological significance for SWDs generation of a decreased GABAB autoreceptor sensitivity of NRT neurons remains to be established.
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ACKNOWLEDGMENTS |
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Present address of C. I. Badiu: CNRS UMR 5543, Université Victor Segalen, Bordeaux 2, 146 Rue Léo Saignat, 33076 Bordeaux Cedex, France.
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FOOTNOTES |
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Address for reprint requests and other correspondence: N. Leresche, Neurobiologie des Processus Adaptatifs, UMR 7102 CNRS, Université Pierre et Marie Curie-Paris 6, 9 quai St Bernard, 75252 Paris Cedex 05, France (E-mail: nathalie.leresche{at}snv.jussieu.fr)
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