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Department of Neurology, University of Virginia, Health Sciences Center, Charlottesville, Virginia
Submitted 7 February 2007; accepted in final form 6 September 2007
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ABSTRACT |
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INTRODUCTION |
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; Hudson et al. 1993; Margerison and Corsellis 1966). Although much research on limbic epilepsy has focused on alterations in the hippocampus, the widespread limbic pathology associated with this syndrome in humans and in animal models suggests that limbic epilepsy should be viewed as a disorder of the limbic system as a whole with potential involvement of extra limbic structures (Bertram 2003; Bertram et al. 1997, 1998) rather than as a syndrome involving a single structure such as the hippocampus.
Subcortical structures such as the basal ganglia and thalamus may play an important role in the evolution and spread of limbic seizures (Blumenfeld et al. 2004) and there is growing evidence to suggest that the dorsal midline thalamus may be an important circuit component in seizures of limbic epilepsy (Bertram et al. 2001; Cassidy and Gale 1998; Patel et al. 1988). This region has many reciprocal connections with the limbic structures and the prefrontal cortex and may be involved in memory, cognition, arousal, and consciousness. Because of the potential role this thalamic region plays in these functions, a better understanding of its physiology is necessary.
We have hypothesized that the thalamolimbic circuits are an important component of limbic epilepsy (Bertram et al. 1998) and have suggested that the midline thalamus may modulate the generation and propagation of seizures (Bertram et al. 2001). Damage of the dorsal midline thalamus has been observed in animal models of epilepsy (Bertram et al. 2001; Brandt et al. 2003; Kubova et al. 2001), as well as humans with limbic epilepsy (Juhasz et al. 1999; Natsume et al. 2003).
There is evidence that altering 
-aminobutyric acid type A (GABAA) receptor mediated inhibition in the dorsal midline thalamus can modulate limbic seizures. In animal models, focal pretreatment of the MD nucleus with GABA-receptor (GABAR) agonists interfered with the development of focally evoked limbic motor seizures (Cassidy and Gale 1998; Patel et al. 1988). These data support the hypothesis that the midline thalamus may play a role in limbic epilepsy.
Despite this evidence for a potential role of GABAergic mechanisms in the modulation of inhibition in the midline thalamus in limbic epilepsy, there are no reports about inhibitory synaptic function in the dorsal midline thalamus. There is heterogeneity of GABAA receptors among the nuclei in the dorsal midline thalamus (Peng et al. 2004; Pirker et al. 2000) and it is well known that limbic epilepsy is associated with changes in the GABAR subunit composition in other regions (Brooks-Kayal et al. 1998; Coulter 2000; Houser and Esclapez 2003; Mtchedlishvili et al. 2001; Peng et al. 2004) that can affect the pharmacology of the receptor. Therefore this initial study focused on characterizing synaptic GABAA receptor mediated inhibitory postsynaptic currents (IPSCs) in the mediodorsal (MD) and paraventricular (PV) neurons in control animals and epileptic animals.
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METHODS |
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Animal preparation
Adult male Sprague–Dawley rats were made epileptic using the continuous hippocampal stimulation method (Lothman et al. 1989). A bipolar electrode was implanted in the left midventral hippocampus under ketamine–xylazine anesthesia using stereotaxic coordinates as described in Paxinos and Watson (2005) (in mm): AP 5.3 posterior to bregma; L 4.9; DV 5.0 below dura; incisor bar at –3.3. One week after surgery, status epilepticus (SE) was induced by stimulating the hippocampus at 50 Hz, 400 µA using 1-ms biphasic square waves in 10-s trains applied every 11 s for 90 min. Self-sustaining limbic status epilepticus developed during the stimulation and lasted 10–14 h. Approximately 4–6 wk later, animals developed spontaneous limbic seizures, which were documented by either continuous electroencephalogram (EEG) monitoring or direct observation of behavioral seizures (Rempe et al. 1997). In our model of epilepsy, we have a recognized failure rate in about 20% of all stimulated rats. They have normal afterdischarge thresholds, but do not develop SE with continuous EEG seizure activity after stimulation, and they do not become epileptic. Presently, we do not know any another basis for this, other than inherent biological variability. We included this group of animals to control for the effect of stimulation. Results from these two groups were analyzed separately and were subsequently combined after no differences were found. Epileptic rats were used 
4 mo after stimulation to ensure that they had reached a comparable seizure maturity (Bertram and Cornett 1994). All groups were age matched.
Thalamic slice preparation
Animals were anesthetized with halothane before decapitation and brains were immersed into a low NaCl, high-sucrose ice-cold oxygenated dissection buffer containing (in mM) 65.5 NaCl, 2 KCl, 5 MgSO4, 1.1 KH2PO4, 1 CaCl2, 10 dextrose, 25 NaHCO3, and 113 sucrose (300 mOsm). The block containing the midline thalamus was mounted on a vibratome stage (Camden Scientific Instruments, Cambridge, UK) and cut at 300 µm coronally. The slices were kept in oxygenated artificial cerebrospinal fluid (ACSF) at 29°C for 1 h before being transferred to the recording chamber. The oxygenated ACSF contains (in mM) 127 NaCl, 2 KCl, 1.5 MgSO4, 25.7 NaHCO3, 10 dextrose, and 1.5 CaCl2 (pH 7.4; 300 mOsm).
Recording and data acquisition
The slices were continuously perfused with oxygenated ACSF. The patch electrodes were prepared from thick-walled borosilicate glass (World Precision Instruments, Sarasota, FL), pulled on a horizontal Flaming-Brown microelectrode puller (model P-97, Sutter Instrument, Novato, CA) using a two-stage pull protocol. Patch electrodes were filled with internal solution containing (in mM) 153.3 CsCl, 1.0 MgCl2, 10 HEPES, 5.0 EGTA, and 2 ATP-Mg (buffered to pH 7.2 with CsOH, 285 mOsm) and had a resistance of 2–4 M
. Biocytin (0.005%) was included in some recordings to permit confirmation of cell location. Whole cell voltage-clamp recordings were made using an Axopatch 1D amplifier (Molecular Devices, Sunnyvale, CA). The temperature in the recording chamber was maintained at 24°C using an inline heating system coupled with an automatic temperature controller (Warner Instruments, Hamden, CT). Although there were clear differences in the recordings when the bath temperature was increased to 37°C, there was an associated significant deterioration in our ability to hold the cells and in the recording quality. The recordings were performed under visual control through a video monitor to identify neurons by position. Cells were voltage clamped to –60 mV and, for the combination of the internal and external solutions, the calculated ECl– was 0 mV and the experimental ECl– was +5 mV. Spontaneous inhibitory postsynaptic currents (sIPSCs) were recorded in the presence of D-6-cyano-7-nitroquinoxaline-2,3-dione (DNQX, 20 µM, 
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate antagonist) and D-(–)-2-amino-5-phosphonovaleric acid (D-AP5, 50 µM, N-methyl-D-aspartate antagonist) (both from Tocris, Ellisville, MO) to inhibit glutamate receptors. Miniature inhibitory postsynaptic currents (mIPSCs) were obtained in the presence of glutamate blockers by blocking action potentials with 3 µM tetrodotoxin (TTX). After access was obtained, the series resistance was compensated between 70 and 80% following capacitance compensation. Whole cell capacitance measurements were determined from amplifier settings after canceling the capacitative transients. Access resistance was measured and monitored by measuring the size of capacitance transients in response to a 5 mV hyperpolarizing step. Currents were low-pass filtered at 5 kHz and digitized at a frequency of 10 kHz using a 1322A Digidata (Axon Instruments, Burlingame, CA) A/D converter. The currents were recorded using pClamp 8.2 software (Molecular Devices) 10 min after access was obtained to allow the internal contents of the pipette to equilibrate with the cell contents. Recordings in which access resistance changed >20% were rejected.
Biocytin labeling
Biocytin labeling was performed as previously described (Zhang 2004). Briefly, slices were removed from the recording chamber and left at 30°C for 1 h in ACSF, and then fixed by immersion in 4% paraformaldehyde in 0.1 M phosphate-buffered saline (PBS) overnight at 4°C, and then rinsed twice in 0.1 M PBS. Endogenous peroxidase activity was quenched by incubating slices in a 3% H2O2 and 10% methanol in PBS, followed by 5-min wash in PBS plus 0.1% Triton X-100. The slices were then incubated in streptavidin-conjugated peroxidase (2 µg/ml) in PBS containing 2% Triton overnight at 4°C, rinsed five times in PBS plus 0.1% Triton, and reacted with 3,3'-diaminobenzidine tetrahydrochloride (0.06%) and H2O2 (0.003%) in PBS. The slices were then mounted on slides, air dried overnight, dehydrated through an ethanol series (70–100%), followed by xylene, embedded in Permount, and coverslipped.
Data analysis
The currents were analyzed using the Mini Analysis software (Synaptosoft, Decatur, GA). All events were identified visually to avoid against errors in detection by automation. The threshold for detection of currents was set at threefold the root-mean-square baseline noise, which was measured for each epoch of recording. All events were identified for determination of frequency, amplitude, and rise times, although decay constants were determined from events that did not have another overlapping event on the decay phase of the former. Charge transfer for each event was calculated by the software as the integral under the current–time trace (pA·ms) during an event. We multiplied it by the frequency of events for the particular recording and represented it as nA·min for net charge transfer. Analysis of sIPSCs and mIPSCs were similar, except where noted.
The mIPSC population amplitude was described by the mean of their median values because the amplitudes may not be normally distributed due to potential loss of smaller currents in the background noise. The time-to-decay for sIPSCs was taken as the time from the peak to a point one third of the peak value; mIPSCs were determined by fitting with a biexponential function, with 
1 and 2 representing the fast and slow decay time components, respectively. Weighted decay (w) was calculated using the formula
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1 and 2 represent the fast and slow decay times, respectively; and A1 and A2 represent the amplitude of the fast and slow components, respectively. Frequencies were compared between groups using the nonparametric Kolmogorov–Smirnov (K-S) test, and IPSC amplitudes and their kinetics were compared with an unpaired t-test. Statistical comparisons were performed using Prism software (GraphPad, San Diego, CA). All data are represented as means ± SE; a value of P < 0.05 was considered statistically significant. |
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RESULTS |
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). For purposes of this study, the MD was defined as lying between the lateral and medial edge of the habenula and extending 1 mm below the habenula. The area between the medial inferior corners of habenulae and immediately below the third ventricle for 0.75 mm was defined as the PV nucleus (Fig. 1 C).
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50%). This included 99 cells from control animals (46 MD, 53 PV) and 60 cells (25 MD, 35 PV) from epileptic animals. Of these, 75 neurons (47%), including 57 cells (32 MD, 25 PV) from control and 18 cells (8 MD, 10 PV) from epileptic animals, were successfully stained. To find whether there was a shift in the proportion of representation of specific cell types in epilepsy, we further classified the neurons by their cell types. In the MD, 25 cells from control and 4 cells from epileptic animals had a stellate morphology, whereas 7 control cells and 4 cells from epileptic animals had a fusiform appearance. In the PV, 16 cells from control and 4 cells from epileptic animals had a stellate morphology. The 15 fusiform neurons included 9 cells from control and 6 cells from epileptic animals. Based on the ratio of filled cells to stained neurons, it appears that we had greater success in recovering filled neurons from control animals (60%) than those obtained from epileptic animals (33%). Within this limited sample size of our classified cell types, we could not find a statistically significant shift in the proportion of a specific cell type in epilepsy in both regions, as determined by the Fisher's exact test, although future studies with larger sample size may indicate otherwise. In the MD, the sIPSCs (Fig. 2 A, Table 1) for epileptic animals were less frequent without alteration in the amplitude compared with controls. Comparison of cumulative probability plots of frequencies (Fig. 2D) revealed a significantly (P < 0.001, K-S test) greater interevent interval in epileptic animals. A comparison of the cumulative amplitude distribution between data obtained from neurons of control and epileptic animals revealed no alterations in event amplitudes in epilepsy (Fig. 2E). In contrast, cells from the PV nucleus of epileptic animals (Fig. 2B) had more frequent sIPSCs (Fig. 2F) with larger amplitudes than those recorded from controls (Table 1). A cumulative distribution histogram of amplitudes (Fig. 2G) revealed a clear right shift toward events with larger IPSC amplitude in the neurons of epileptic animals compared with controls.
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To determine the basis of prolonged rise time of sIPSCs in recordings from the neurons of epileptic animals, we tested whether there was a shift in the proportion of events under specific rise time subpopulations. The pooled rise times were binned at 2 ms intervals, such that there were three subpopulations of rise times: <2 ms, 2–4 ms, and >4 ms. There was no significant shift in the proportion of events in each group in MD and PV neurons for s- and mIPSCs (Fig. 4, A–D).
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w) was significantly faster in PV neurons from epileptic animals compared with that of controls. Data from the fitting of the IPSCs to a biexponential function suggest a significantly faster 1 component in epilepsy, whereas the 2 component remained unchanged (Table 2, Fig. 5D). Finally, there was no difference in net charge transfer between MD neurons from control and epileptic animals. However, there was a significant (P < 0.01, unpaired t-test) increase in net charge transfer in PV neurons of epileptic animals compared with that of controls (Tables 1 and 2).
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DISCUSSION |
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The role of IPSCs in the maintenance of the inhibitory state in vivo is of interest. Previous studies suggest that IPSCs help mediate background inhibition (Otis et al. 1991; Salin and Prince 1996), which may reduce the network sensitivity to excitatory input (Paré et al. 1998). IPSC parameters can be influenced by a number of pre- and postsynaptic factors (Edwards et al. 1990; Otis and Mody 1992; Ropert et al. 1990). The frequencies, for example, are principally influenced by the number of presynaptic inputs and presynaptic release activity. The amplitudes of the IPSCs are influenced not only by quantal content and size, but also by the number, availability, and type of postsynaptic receptors. The release synchrony, the location of synapse, and postsynaptic receptor properties of the neurons influence the rise time of the IPSCs, whereas the time course of neurotransmitter in the synapse and postsynaptic receptor changes, including subunit composition shape the decay of IPSCs. Using changes in a variety of these IPSC parameters as functional indicators of changes in GABAA-receptor–mediated synaptic activity, previous studies have shown that GABAA-receptor–mediated inhibition is altered in limbic epilepsy. For instance, a reduction in IPSC frequency has been reported to occur in hippocampal dentate granule cells of epileptic animals (Kobayashi and Buckmaster 2003), whereas there was an increase in IPSC frequency in the CA1 interneurons (Cossart et al. 2001; Stief et al. 2007). Similarly, changes in IPSC amplitude in the hippocampal neurons in epilepsy have been reported by other investigators (Brook-Kayal et al. 1998; Gibbs et al. 1997; Kobayashi and Buckmaster 2003) due to potential changes in the number of postsynaptic receptors (Nusser et al. 1998), GABAA receptor subunit alteration (Brooks-Kayal et al. 1998), or the size of presynaptic quantal contents (Boulland et al. 2007). Changes in rise and decay kinetics of the IPSCs in epilepsy, due to potential loss of a subset of synapses or altered postsynaptic receptor properties, were also previously reported (Coulter 2000; Kobayashi and Buckmaster 2003; Mtchedlishvili et al. 2001; Sun et al. 2007).
Our data demonstrate clear, region-specific differences in epilepsy in sIPSCs and mIPSCs mediated by the GABAA receptors. Because we had earlier (Bertram et al. 2001) found no differences between the neurons of control and epileptic animals in the passive current–voltage relationship, and because there were no significant differences in whole cell capacitance observed in the present study, the changes in the IPSC characteristics can most likely be attributed to alterations in synaptic transmission in the two regions rather than altered biophysical properties of the neurons in these regions. However, we cannot assign specific mechanistic bases to our findings, which may involve both pre- and postsynaptic factors. We also observed that the mean IPSC frequencies recorded from the neurons of the MD and PV from control animals were much lower and rise times much slower than those reported for the reticular nucleus of the thalamus and the ventrobasal thalamus (Zhang et al. 1997). Differences in the age of animals, afferent connectivity, and/or release properties may underlie these differences.
A potential shift in the relative proportion of cell types in epilepsy may also account for the findings of this study. Our analysis of the IPSC parameters by region and cell types gave us a conflicting picture with some concordant changes between cell types. Indeed, there was a trend toward decrease in sIPSC frequency and net charge transfer in the fusiform neurons in the MD in epilepsy, suggesting a potential shift in cell type proportion in epilepsy. However, we did not find any statistically significant shift in the relative proportions of cell types in epilepsy in the MD or the PV region. Nevertheless, one should view these observations cautiously because the sample sizes are relatively small. To evaluate this question properly, a focused anatomical should be performed; however, this is beyond the scope of the present study.
Although there is good evidence from rats that these nuclei are a component of the limbic seizure circuit (Bertram et al. 2001; Cassidy and Gale 1998; Patel et al. 1988), there is also evidence from humans to suggest the decreased benzodiazepine ligand binding in the MD in patients with limbic epilepsy (Juhasz et al. 1999). Taken together, these reports underline the importance of GABAA receptor mediated inhibition in this region in epilepsy. Nevertheless, there are currently no reports on changes in synaptic GABAA receptor mediated inhibition in limbic epilepsy in this region. The findings of this study are of potential importance to the pathophysiology of limbic epilepsy due to the widespread connections of these thalamic neurons (Groenewegen 1988; Krettek and Price 1977; Kuroda et al. 1998; Pirot et al. 1994; Ray and Price 1992) to a number of regions associated with limbic epilepsy. However, because the intricacies of these primary seizure circuits are at the moment not well understood, it is difficult to predict the overall functional significance of these changes with regard to the pathophysiology of limbic epilepsy. The neurons of the MD and PV nucleus are hyperexcitable in limbic epilepsy (Bertram et al. 2001). In this circumstance, the enhanced inhibition in the PV may be a compensatory homeostatic response to increased excitation in an attempt to maintain the overall balance of excitation and inhibition in this region. Alternately, the pathology to the MD neurons in epilepsy (Bertram and Scott 2000) may have led to preferential targeting of some afferents destined for the MD onto the PV, leading to hyperinnervation of the PV. Such a mechanism has been described in a model of experimental epileptic microgyri where there was a hyperinnervation of the paramicrogyral region surrounding the lesioned microgyri (Prince and Jacobs 1998). On the other hand, an unaltered net inhibition in the MD may in fact suggest a failure in inhibition in these hyperexcitable neurons that may favor enhanced excitability.
In summary, the results of this initial examination of GABAergic activity in the limbic thalamus have shown a complex and regionally variable series of changes in the IPSCs in the dorsal midline thalamus in limbic epilepsy. Overall, there appears to be enhanced GABAA receptor mediated synaptic activity in the PV, with fewer changes in the MD. The data also raise the possibility that there may be a shift in the relative proportion of neuronal cell types in the MD in epilepsy. To put the changes in a more precise context with regard to epilepsy, the results of this preliminary study must be examined in more extensive studies evaluating potential changes in the anatomy, and pharmacology of GABAA receptors, response to antiepileptic drugs, and overall circuit function, which will be addressed in future reports. These studies will provide a better defined role of these structures in limbic epilepsy.
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GRANTS |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address for reprint requests and other correspondence: E. H. Bertram, Department of Neurology, PO Box 800394, University of Virginia, Health Sciences Center, Charlottesville, VA 22908 (E-mail: ehb2z{at}virginia.edu)
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ABSTRACT
INTRODUCTION
