Elsevier

Epilepsy Research

Volume 32, Issues 1–2, 1 September 1998, Pages 93-103
Epilepsy Research

Interneurones are not so dormant in temporal lobe epilepsy: a critical reappraisal of the dormant basket cell hypothesis

https://doi.org/10.1016/S0920-1211(98)00043-6Get rights and content

Abstract

One axiom at the basis of epilepsy research is that there exists an imbalance between excitation and inhibition. This abnormality can be achieved by an increase of excitation on principal cells, a decreased inhibition (i.e. disinhibition) or both. This review focuses on dysfunction of inhibition, and in particular on the `dormant basket cell hypothesis'. This hypothesis states that, (1) interneurones are functionally disconnected from excitatory afferents, resulting in hyperexcitability of principal neurones and loss of paired pulse inhibition, (2) when properly activated, interneurones can still perform their task, i.e. suppress epileptiform activity and restore paired pulse inhibition. The aim of this review is to discuss the evidence in support of the `dormant basket cell hypothesis'. We will first discuss the rationale underlying the hypothesis and the criteria needed to validate the hypothesis. We will then show that, (1) the key experimental data offered in support of the hypothesis (Bekenstein and Lothman, 1993. Dormancy of inhibitory interneurones in a model of temporal lobe epilepsy. Science 259, 97–100; Sloviter, 1991. Permanently altered hippocampal structure, excitability, and inhibition after experimental status epilepticus in the rat: the `dormant basket cell' hypothesis and its relevance to temporal lobe epilepsy. Hippocampus 1, 41–66) are difficult to interpret, and (2) recent recordings from interneurones in epileptic tissue argue against the hypothesis. The `dormant basket cell hypothesis' is then discussed in the broader context of disinhibition.

Section snippets

Foreword

In 1877, Claude Bernard wrote about the Principles of Applied Medicine: `The experimental method is nothing but bringing observation and experiment into operation in order to get access to scientific truth. Some use the results of observation and experiment to build theories that they no longer put to test. They could be called a priorists. Instead, one's inferences are to be tested by new experiments. This is the true experimental method everyone knows about and which M. Cheuvreul calls the a

What is the dormant basket cell hypothesis?

As stated by Sloviter (1991b), the dbch `implies that although seizure-resistant GABA neurones survive, they are hypofunctional because they have lost critical excitatory inputs' and that `a reversible loss of inhibition can occur in experimental tissues in which most GABA neurones appear, at least morphologically, to be relatively normal'. Thus, the dbch contains TWO aspects that cannot be dissociated: `the loss of excitatory systems that normally evoke inhibition' and `the reversibility of

Loss of functional inhibition

Let us assume that interneurones have lost a critical set of excitatory afferents. What data support the view that this loss results in dysfunction of inhibition and hyperexcitability in principal cells?

In a subsequent electrophysiological study, Sloviter (1991b)examined the predictions of this disconnection theory in dentate granule cells and CA1 pyramidal neurones. Extracellular recordings of population spikes were obtained in an in vivo kindling model of TLE. Measurement of population spikes

Do the results provided by Bekenstein and Lothman demonstrate that inhibitory interneurones are dormant?

Intracellular recordings of CA1 pyramidal cells were performed in vitro in a different kindling model of TLE (Bekenstein and Lothman, 1993). If the slice tissue was stimulated `far' from the site of the recording electrode, IPSPs were not seen. However, when stimulations were applied closer to the recording site, IPSPs could be measured in the presence of glutamatergic antagonists. These data were interpreted to support the concept of functional disconnection of interneurones from their

What should be done to prove the dbch?

Since the hypothesis contains two parts, each of them should be addressed.

(1) First, the dbch proposes that some interneurones have lost a critical set of excitatory afferents. This could occur via an anatomical loss of excitatory synapses and/or a decrease of their response (long-term depression of synaptic responses, postsynaptic downregulation of AMPA/NMDA receptors, declustering, etc.). These modifications should affect more the interneurones than the principal cells, so that interneurones

What do the recordings of interneurones in chronic models of TLE tell us?

So far, five studies have reported the recording of interneurones in the CA1 area in chronic animal models of TLE (Franck et al., 1988, Nakajima et al., 1991, Morin et al., 1996, Esclapez et al., 1997, Rempe et al., 1997).

(1) In the bilateral kainic acid (KA) model of TLE, five putative interneurones were recorded 2–4 months after KA injection, and ten neurones 2–4 weeks after the lesion (four of which were morphologically identified post hoc as interneurones) (Franck et al., 1988). All five

Are these results consistent with the two components of the dbch?

(1) Functional disconnection of interneurones from a critical set of excitatory afferents. None of these studies directly addressed this issue. However, known morphological facts allow some speculation. In all these animal models of TLE (except for the pilocarpine model), there is a massive loss of CA3 pyramidal cells ipsilaterally to the lesion (Nadler et al., 1978, Sloviter, 1987). Thus, the resulting loss of Schaffer collaterals, which provide a major excitatory input to interneurones (

The dbch and the concept of disinhibition

As stated previously, the general concept of disinhibition does not seem to be a fundamental feature of epilepsy. Many recent studies lead to the conclusion that inhibition is either increased or unaffected at the level of the GABAergic synapses on principal cells. That is, if inhibition is decreased, it does not involve a downregulation of interneurone function. Thus, the fate of inhibition in epileptic tissue becomes a highly complex issue for which a straightforward and unique answer seems

Conclusion

(1) Disinhibition per se does not seem critical for epileptogenesis, especially given that compensatory mechanisms may result in enhanced inhibition. Thus, the concept of dormant interneurones as an explanation for epileptiform activity is certainly not universally applicable.

(2) The initial experiments addressing the dbch are difficult to interpret because of the complexities of the experimental paradigms.

(3) If the interneurones recorded by various research groups are representative of the

Acknowledgements

Supported by Parke Davis. Parts of the points discussed in this review have been raised during two sessions about the dormant basket cell hypothesis at the 1997 Spring Epilepsy Conference in the Grand Cayman and the 1997 WONOEP IV in Adare, Ireland. The authors are indebted to I. Mody, E. Bertram, R. Dingledine, P. Schwartzkroin and D. Coulter for their helpful comments and stimulating questions during discussion sessions.

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