Ontogeny of altered synaptic function in a rat model of chronic temporal lobe epilepsy

Abstract

In the limbic status model of chronic temporal lobe epilepsy, hippocampal stimulation induces acute status epilepticus in rats; recurrent, spontaneous seizures develop following an asymptomatic silent period lasting several weeks. Previous work has shown increased excitability and decreased inhibition in CA1 pyramidal neurons in chronically epileptic animals. To determine the relationship of altered cellular responses to seizure onset, in vitro intracellular recording was used to follow the evolution of changes in synaptic physiology occurring during the seizure-free silent period. Pyramidal cells displayed increasing epileptiform activity throughout the period investigated, 3–14 days following status; the mean number of evoked action potentials from 1.1±0.05 in control cells to 2.4±0.4 early (3 days after status) and 4.3±0.7 late (14 days) in the silent period. Monosynaptic inhibitory postsynaptic potentials mediated by γ-aminobutyric acid-A receptors in silent period cells differed markedly from controls. Area, rise time, and duration of these potentials decreased by 40–60% within 3 days following status and to values commensurate with chronically epileptic animals in 7 to 10 days. γ-Aminobutyric acid-B receptor-mediated IPSPs diminished more gradually in the silent period, reaching a minimum at day 14. In contrast, presynaptic γ-aminobutyric acid-B receptor function showed maximum impairment 3 days after status. The benzodiazepine type 1 receptor agonist zolpidem reduced hyperexcitability in both silent period and chronically epileptic cells, but was more effective at unmasking the underlying IPSP in silent period neurons. The results indicate that changes in different components of pyramidal cell inhibitory synaptic physiology associated with chronic epilepsy in this model evolve individually at different rates, but are all complete before seizure onset. Although the results do not imply causality, they do suggest that the development of physiological changes in CA1 pyramidal cells may contribute to the lag period preceding the onset of chronic seizures.

Introduction

The epilepsies encompass more than 40 identified disorders [44]characterized by the chronic spontaneous recurrence of seizures implying a sustained abnormality of the brain [14]. Approximately 30% of adult epilepsies remain refractory to treatment with anti-epileptic drugs [12]; of these uncontrolled epilepsies, complex (consciousness-impairing) partial (focal origin) seizures arising from the mesial temporal lobe are especially troublesome in terms of medical intractability and the number of patients afflicted [34].

A mesial temporal lobe epilepsy syndrome (mTLE) has been described which is often characterized by the occurrence of an initial central nervous system insult early in life, a seizure-free `silent' period of several months or years, the eventual onset of intractable complex partial seizures, and a good response to surgery 25, 64. In its most common form, mTLE is associated with mesial temporal sclerosis, the loss of principal neurons with accompanying gliosis in hippocampus and other temporal lobe structures 2, 3, 10. The lack of effective drug therapy in mTLE often necessitates surgical removal of mesial temporal lobe structures [63]. A better understanding of the changes occurring during the silent period which may support the genesis of chronic spontaneous seizures could lead to the development of preventative therapies.

This study examines the evolution of one aspect of altered synaptic physiology in the silent period employing the electrogenic post-SSLSE animal model of mTLE. The post-SSLSE model is characterized by anatomical abnormalities (Ammon's horn sclerosis, gliosis, proliferation of dentate gyrus granule cell axon collaterals) and spontaneous recurrent seizures ensuing from a period of self-sustaining (continuing 6–18 h post-stimulus) limbic status epilepticus (SSLSE) 9, 35, 36, 42. Bertram and Cornett [7]have documented a stereotyped progression from the initial bout of status epilepticus, through onset of electrographic seizures, culminating in chronic spontaneous motor seizures. This study found average intervals of status-to-first electrographic seizure and first electrographic-to-first motor seizure of 13 and 15 days, respectively. Physiologically, the model is typified in the chronic state by enhanced excitability and reduced inhibition in several hippocampal/parahippocampal regions 4, 37, 41, 55. Recent studies have revealed anomalies in glutamatergic neurotransmission [37]and γ-aminobutyric acid (GABA)-dependent processes, mediated by both GABA_A and GABA_B type receptors, in the CA1 subfield of the hippocampus 39, 40. However, it is unknown whether these GABAergic abnormalities develop before or after seizure onset. The goal of the present study was to examine the progression of these changes during the silent period between status epilepticus and initial seizure appearance to define alterations preceding, and thus possibly contributing to, the onset of seizures. Synaptic physiology was examined at several time points in the 14 days immediately following status. Our results indicate that changes in CA1 synaptic efficacy are largely complete before seizures begin in this model of mTLE suggesting a possible role for decreased GABAergic inhibition and enhanced glutamatergic excitation in the induction of epileptogenesis.