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EDITORIAL FOCUS
). Since the introduction of high-resolution whole cell patch clamping in brain slices (Edwards et al. 1990), mini analysis has also been employed in epilepsy research, primarily to aid the identification of pre- and postsynaptic alterations in various seizure paradigms in different brain areas involved in convulsions. However, no clear, unifying picture has yet emerged regarding the link between changes in miniature synaptic events and the factors that modify seizure thresholds during the process of epileptogenesis following an initial insult. In this issue of the Journal of Neurophysiology (p. 952–960), Shao and Dudek take us a step closer to this elusive goal by demonstrating that, in spite of significant decreases in the frequency of miniature GABAA receptor-mediated inhibitory postsynaptic currents (mIPSCs) recorded from the granule cells of the dentate gyrus in epileptic animals, the frequency of the action potential-dependent or "spontaneous" IPSCs (sIPSCs) remains unchanged, suggesting the involvement of certain compensatory processes that enable the network to maintain spontaneous GABAergic activity levels similar to controls. The authors used the classical limbic convulsant drug kainate to induce repeated, prolonged seizures (i.e., status epilepticus), which, several weeks later, after a quiescent, so-called "latent" period, resulted in the appearance of recurrent, robust, spontaneous motor seizures (i.e., epilepsy). To gauge how the GABAergic control of the dentate "gate" (thought to be a major regulator of activity patterns in the limbic system) was altered in this model of epilepsy, either 4–7 days (acute group) or >3 mo (chronic group) after the initial insult, whole cell patch-clamp slice recordings of sIPSCs were performed, followed by the recordings of mIPSCs in the same granule cells after switching to a perfusing solution that included the Na+-channel blocker tetrodotoxin.
In the acute group, recorded a few days after the kainate-induced status epilepticus, there was a significant reduction in the frequency of mIPSCs. This reduction was persistent because it was also present in the chronic group, even after the recurrent spontaneous motor seizures appeared. However, the frequency of the sIPSCs remained completely unaltered at both the early and late time points in spite of the significantly depressed rate of miniature events. Further analysis revealed that, with the surprising exception of increased peak amplitude and decay time constant in the acute-mIPSC group, there were no other alterations in either time points for mIPSCs or sIPSCs.
How can one interpret these findings? Because prior research had shown that kainate treatment resulted in the loss of certain classes of interneurons from the dentate hilus that normally provide a significant portion of the GABAergic synaptic inputs to dentate granule cells, the authors suggested that the decreased mIPSC frequency most likely resulted from the partial loss of the presynaptic hilar interneurons, although alternative explanations, such as a decreased probability of GABA release, could not be fully excluded (note that the increased amplitude in the acute mIPSCs indicated that the decreased mini frequency was not simply related to a change in the percent of detectable events). Furthermore, the authors interpreted the unchanged sIPSC frequency that occurred concurrently with the decreased mIPSC frequency as indicating that the surviving interneurons increased their spontaneous firing rates, although changed release probabilities again remained an untested possibility.
As is frequently the case with research into basic mechanisms of a complex disease such as epilepsy, the current results share both similarities and differences with previous findings regarding the alterations of mIPSCs in different hippocampal regions in various experimental seizure paradigms (e.g., Chen et al. 1999; Hirch et al. 1999). Although gaining a precise knowledge of the changes in spontaneous action potential-dependent and -independent GABA release is undoubtedly important, the message that is emerging from related studies in the field is that the mIPSC and sIPSC data alone are not sufficient to arrive at a cohesive interpretation of how the GABAergic system gets modified by the seizures. The main reason is that the baseline properties of mIPSCs and sIPSCs can be modulated by additional mechanisms that make it difficult to predict the functional relevance of changes in mIPSCs and sIPSCs. For example, after kindling in dentate granule cells, increases in mIPSC amplitude can be counteracted by a variety of post- and presynaptic factors, including a seizure-induced switch in GABAA receptor subunits that make the IPSCs sensitive to blockade by zinc released from the aberrantly sprouted, zinc-containing axons of granule cells in epileptic animals (Buhl et al. 1996).
However, in spite of the lack of an easy way to determine the functional relevance of seizure-induced alterations in spontaneous synaptic events, the importance of understanding how minis change in epilepsy, if anything, has actually increased. The rise in the fortunes of minis is due to the fact that they are increasingly being recognized as events with real functional relevance, indicating minis may be more than convenient tools for electrophysiologists. For example, recent studies suggest that mIPSCs can generate significant inhibitory tone in certain neurons, have important roles in development, in postsynaptic receptor clustering as well as in spine maintenance (see Zucker 2004). On the other hand, there is also recent evidence that suggest that mIPSCs and sIPSCs are less closely related than previously thought because minis seem to arise from a vesicle pool that is distinct from those released by action potentials (Sara et al. 2005).
Like most important studies, the current paper by Shao and Dudek raises a number of additional questions. Perhaps the most interesting one concerns the exact nature of the relationship between the activity-dependent synaptic homeostatic mechanisms (e.g., Kilman et al. 2002) and the changes in miniature events observed after seizures. Do the homeostatic processes proceed unchanged in the epileptic brains or do the mechanisms that provide homeostasis in control networks become maladaptive during the process of epileptogenesis? For example, do the activity sensors that are thought to be crucial for homeostatic mechanisms get modified as a result of seizure-induced alterations in, for example, Ca2+ buffering (Nagerl et al. 2000)? We do not yet know the answers to these questions, but it is likely that minis will continue to play a big role in understanding the generation of epilepsy for a long time to come.
Department of Anatomy and Neurobiology, University of California, Irvine, California
Address for reprint requests and other correspondence: J. C. Echegoyen, Dept. of Anatomy and Neurobiology, University of California, Irvine, CA 92717 (E-mail: jechegoy{at}uci.edu)
REFERENCES
Buhl EH, Otis TS, and Mody I. Zinc-induced collapse of augmented inhibition by GABA in a temporal lobe epilepsy model. Science 271: 369–373, 1996.[Abstract]
Chen K, Baram TZ, and Soltesz I. Febrile seizures in the developing brain result in persistent modification of neuronal excitability in limbic circuits. Nat Med 5: 888–894, 1999.[CrossRef][ISI][Medline]
Edwards FA, Konnerth A, and Sakmann B. Quantal analysis of inhibitory synaptic transmission in the dentate gyrus of rat hippocampal slices: a patch-clamp study. J Physiol 430: 213–249, 1990.
Hirsch JC, Agassandian C, Merchan-Perez A, Ben-Ari Y, DeFelipe J, Esclapez M, and Bernard C. Deficit of quantal release of GABA in experimental models of epilepsy. Nat Neurosci 2: 499–500, 1999.[CrossRef][ISI][Medline]
Katz B. The Release of Neural Transmitter Substances. Springfield, IL: CC Thomas, 1969.
Kilman V, van Rossum MC, and Turrigiano GG. Activity deprivation reduces miniature IPSC amplitude by decreasing the number of postsynaptic GABA(A) receptors clustered at neocortical synapses. J Neurosci 22: 1328–1337, 2002.
Nagerl UV, Mody I, Jeub M, Lie AA, Elger CE, and Beck H. Surviving granule cells of the sclerotic human hippocampus have reduced Ca(2+) influx because of a loss of calbindin-D(28k) in temporal lobe epilepsy. J Neurosci 20: 1831–1836, 2000.
Sara Y, Virmani T, Deak F, Liu X, and Kavalali ET. An isolated pool of vesicles recycles at rest and drives spontaneous neurotransmission, Neuron 45: 563–573, 2005.[CrossRef][ISI][Medline]
Shao LI and Dudek FE. Changes in mIPSCs and sIPSCs after kainate treatment: evidence for loss of inhibitory input to dentate granule cells and possible compensatory responses. J Neurophysiol 94: 952–960, 2005.
Zucker RS. Minis: whence and wherefore? Neuron 45: 482–484, 2004.
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  A. Rodriguez-Moreno Changes in mIPSCs and sIPSCs after kainate treatment: possible actions mediated by the direct activation of kainate receptors J Neurophysiol, July 1, 2006; 96(1): 505 - 505. [Full Text] [PDF]
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