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The Role of Extrasynaptic GABAA Receptors in Focal Epilepsy

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Extrasynaptic GABAA Receptors

Part of the book series: The Receptors ((REC,volume 27))

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Abstract

Focal epilepsy can result from both genetic and environmental factors. Acquired focal epilepsy occurs following a specific brain insult such as stroke, head injury or prolonged seizures (status epilepticus). The time from the insult to the development of seizures is termed the epileptogenic period during which there are changes in connectivity, neurotransmission and neuronal excitability.

Epileptogenesis has conventionally been viewed as being associated with increased excitation and a loss of inhibition. This view has been reappraised in recent years due to a better understanding of the multifaceted roles of GABAergic signalling. There is growing evidence that loss of synaptic GABAA receptor-mediated inhibition observed in animal models of temporal lobe epilepsy is accompanied by compensatory upregulation of tonic currents mediated by extrasynaptic GABAA receptors.

Here, we provide evidence for such a change in GABAA receptor-mediated inhibition during epileptogenesis and speculate on the possible functional impact that such a shift in inhibition will have. In particular, we argue that shifts from phasic to tonic inhibition in the hippocampus will lead to a maintenance of “inhibition” of the network but will alter network gain, decreasing network stability. Furthermore, changes in the subunit composition of extrasynaptic GABAA receptors during epileptogenesis have implications for targeted pharmacotherapy of epilepsy.

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Authors and Affiliations

  1. Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK

    Matthew C. Walker & Ivan Pavlov

Authors
  1. Matthew C. Walker
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  2. Ivan Pavlov
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Corresponding author

Correspondence to Matthew C. Walker .

Editor information

Editors and Affiliations

  1. Neuroscience and Mental Health Research Institute, Institute of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, United Kingdom

    Adam C. Errington

  2. Dept. of Physiology & Biochemistry, University of Malta, Msida MSD, Malta

    Giuseppe Di Giovanni

  3. School of Biosciences, Cardiff University, Cardiff, United Kingdom

    Vincenzo Crunelli

Conclusion

Conclusion

The development of focal epilepsy seems to be accompanied by a shift from inhibition mediated by synaptic GABAA receptors to inhibition mediated by extrasynaptic GABAA receptors. This may result in an increase in the gain of the network. This would result in only small increases in input leading to a large increase in the probability of neuronal firing, resulting in potentially more unstable networks that would have the propensity to generate seizure activity.

Alterations in the subunit composition of extrasynaptic GABAA receptors during the development of epilepsy also have significant implications for targeted pharmacotherapy. It is likely that different insults may result in differing degrees and types of subunit alterations, suggesting that more specific therapies may be most useful in epilepsies with distinct and particular aetiologies.

Acknowledgments

This work was supported by Pewterer’s Fellowship to I.P., funding from Wellcome Trust, Medical Research Council (UK), Epilepsy Research UK and European Integrated Project “EPICURE” (EFP6-037315).

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Walker, M., Pavlov, I. (2014). The Role of Extrasynaptic GABAA Receptors in Focal Epilepsy. In: Errington, A., Di Giovanni, G., Crunelli, V. (eds) Extrasynaptic GABAA Receptors. The Receptors, vol 27. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1426-5_10

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