INMED/TINS special issue
Impaired and repaired inhibitory circuits in the epileptic human hippocampus

https://doi.org/10.1016/j.tins.2005.04.002Get rights and content

This review focuses on the epileptic human temporal lobe, primarily on recent findings related to changes in hippocampal GABAergic interneuron circuits that have a central role in epileptogenesis. Relying on correlations to animal studies, we provide a functional interpretation of the different changes in perisomatic inhibition (controlling output synchrony) and dendritic inhibition (controlling input plasticity), and the potential consequences of the loss of interneuron-selective interneurons. The highly heterogeneous, but specific, alterations of GABAergic interneuron circuits have important implications for the pharmacotherapy of epilepsy.

Introduction

The ultimate test of any animal model of epilepsy is to what extent it replicates the sequence of molecular and pathophysiological events, and the pattern of cell death or synaptic reorganization, observed in human epileptic patients. However, examination of human tissue alone, at a single time-point during disease progression, cannot tell us much about the pathological mechanisms involved. Hence, the aim of this review is to correlate human pathology to functional data obtained largely using animal models.

Synaptic reorganization of the epileptic hippocampus and its functional consequences have been studied and reviewed extensively in various animal models, with the aim of shedding light on the causal relationship between characteristic structural changes and hyperexcitability or epileptic seizure activity. Particular attention has always been paid to scrutinizing the fate of inhibitory interneurons, because they have crucial roles in the generation of synchronous population discharge patterns 1, 2, 3, 4 and their impairment is thought to be involved in epileptogenesis and seizure activity 5, 6, 7, 8, 9, 10, 11, 12, 13. Demonstrating a causal relationship between structural changes and hyperexcitability in the human epileptic hippocampus is far more difficult, if at all possible. This could be a reason why reviews discuss the role of interneurons in epilepsy pathology or pathophysiology in humans so much more rarely than in animal models 14, 15, 16, 17, 18, 19. An extensive cross-correlation with experimental epilepsy models is required, taking into account the species differences in interneuron connectivity and molecular architecture. Here, we undertake this challenge; this review summarizes recent data on cell death and synaptic reorganization implicated in GABA neurotransmission in the human epileptic hippocampus, and discusses the potential pathophysiological implications of these data in the light of experimental correlations.

Section snippets

Fate and function of interneurons correlate in the epileptic human hippocampus

Although the majority of glutamic acid decarboxylase (GAD)-positive nonprincipal neurons seems to be preserved in the epileptic human hippocampus 20, 21, 22, the selective loss of some interneuron types has also been reported 16, 18, 19, 23. The impairment of GABA-mediated inhibition that can result from the loss of sensitive interneuron types has been considered as the primary cause of seizure activity. This correlates well with some epilepsy models, in which loss of interneurons and

Preservation of perisomatic inhibition in epilepsy

A well-characterized subset of perisomatic inhibitory cells contains PV in all species examined so far [1]. These neurons include axo-axonic and basket cells in the hippocampi of rodents and primates, and they are responsible for controlling or synchronizing the output of large principal cell assemblies. A decrease in the number of PV-immunoreactive cells has been described in epilepsy models and in the human epileptic hippocampus 19, 23, 45, 46, 47, 48, 49. However, electron-microscopic

Loss and repair of dendritic inhibition

Dendritic inhibitory cells are heterogeneous in their morphology, their neuropeptide or Ca2+-binding protein content, their receptor expression patterns and their localization [1]. They innervate the dendritic region of principal cells regulating the plasticity and efficacy of afferent excitatory (mostly glutamatergic) input. The sensitivity of SST-containing and NPY-containing dendritic inhibitory interneurons has been described both in animal models and human epileptic hippocampi 16, 20, 48,

Impaired synchronization of dendritic inhibitory cells?

Both dendritic and perisomatic interneuron types survive in the epileptic human hippocampus, and their axons are able to sprout, which could compensate to some extent for the impairment of dendritic inhibition. Interneurons in animal models of epilepsy remain functional [30] and display higher levels of mRNA and protein of the GABA-synthesizing enzyme GAD 58, 59. This suggests that the surviving interneurons are recruited by hyperactive recurrent or feedforward excitatory networks, resulting in

Implications for pharmacotherapy

The profound functional heterogeneity of GABAergic interneurons, the diverse reactive changes in their connectivity, and their differential involvement in compensatory or proconvulsive mechanisms, could shed light on why pharmacotherapy relying on enhancing GABA-mediated inhibition frequently fails. To increase the chances that such pharmacotherapy succeeds, synchrony and efficacy of dendritic inhibition should be enhanced, thereby controlling potentiation of excitatory connections, whereas

Acknowledgements

This work was supported by National Institutes of Health Grant MH54671, the Howard Hughes Medical Institute, Országos Tudományos Kutatási Alapprogramok Grants T 46820. We also thank Katalin Lengyel, Emőke Simon, and Győző Goda for technical help.

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