Early loss of interneurons and delayed subunit-specific changes in GABA(A)-receptor expression in a mouse model of mesial temporal lobe epilepsy.

Unilateral injection of kainic acid (KA) into the dorsal hippocampus of adult mice induces spontaneous recurrent partial seizures and replicates histopathological changes observed in human mesial temporal lobe epilepsy (MTLE) (Bouilleret V et al., Neuroscience 1999; 89:717-729). Alterations in pre- and postsynaptic components of GABAergic neurotransmission were investigated immunohistochemically at different time points (1-120 days) in this mouse model of MTLE. Markers of GABAergic interneurons (parvalbumin, calbindin-D28k, and calretinin), the type-1 GABA transporter (GAT1), and major GABA(A)-receptor subunits expressed in the hippocampal formation were analyzed. Acutely, KA injection produced a profound loss of hilar cells but only limited damage to CA1 and CA3 pyramidal cells. In addition, parvalbumin and calbindin-D28k staining of interneurons disappeared irreversibly in CA1 and dentate gyrus (DG), whereas calretinin staining was spared. The prominent GABA(A)-receptor alpha1 subunit staining of interneurons also disappeared after KA treatment, suggesting acute degeneration of these cells. Likewise, GAT1 immunoreactivity revealed degenerating terminals at 24 h post-KA in CA1 and DC and subsided almost completely thereafter. Loss of CA1 and, to a lesser extent, CA3 neurons became evident at 7-15 days post-KA. It was more accentuated after 1 month, accompanied by a corresponding reduction of GABA(A)-receptor staining. In contrast, DC granule cells were markedly enlarged and dispersed in the molecular layer and exhibited a prominent increase in GABA(A)-receptor subunit staining. After 4 months, the dorsal CA1 area was lost almost entirely, CA3 was reduced, and the DG represented most of the remaining dorsal hippocampal formation. No significant morphological alterations were detected contralaterally. These results suggest that loss of hilar cells and GABAergic neurons contributes to epileptogenesis in this model of MTLE. In contrast, long-term degeneration of pyramidal cells and granule cell dispersion may reflect distinct responses to recurrent seizures. Finally, GABA(A)-receptor upregulation in the DG may represent a compensatory response persisting for several months in epileptic mice.

GABAergic neurons and GABA(A)-receptors in temporal lobe epilepsy.

Mesial temporal lobe epilepsy (MTLE) is the most prevalent form of epilepsy, characterized by recurrent complex partial seizures and hippocampal sclerosis. The pathophysiology underlying this disorder remains unidentified. While a loss of benzodiazepine binding sites is a key diagnostic feature of MTLE, experimental studies have shown enhanced inhibitory transmission and increased expression of GABA(A)-receptors, suggesting that compensatory mechanisms are operative in epileptic hippocampus. In the present study, changes in the expression and cellular distribution of major GABA(A)-receptor subunits were investigated in the hippocampus of pilocarpine-treated rats during the phase of spontaneous recurrent seizures. A uniform decrease in GABA(A)-receptor subunit-immunoreactivity was observed in regions of extensive neuronal death (i.e. CA1, CA3, hilus). whereas a prominent increase occurred in the dentate gyrus (DG). Most strikingly, the increase was largest for the alpha3- and alpha5-subunits, which are expressed at very low levels in the DG of control rats, suggesting the formation of novel GABA(A)-receptor subtypes in epileptic tissue. Furthermore, an extensive loss of interneurons expressing the alpha1-subunit, representing presumptive basket cells, was seen in the DG. These changes were very similar to those reported in a novel mouse model of MTLE, based on the unilateral injection of kainic acid into the dorsal hippocampus (Bouilleret et al., 1999). This indicates that the regulation of GABA(A)-receptor expression is related to chronic recurrent seizures, and is not due to the extrahippocampal neuronal damage affecting pilocarpine-treated rats. These results allow causal relationships in the induction and maintenance of chronic recurrent seizures to be distinguished. The loss of a critical number of interneurons in the DG is a possible cause of seizure initiation, whereas the long-lasting upregulation of GABA(A)-receptors in granule cells represents a compensatory response to seizure activity.

[Mumps epidemiology in Switzerland: results from the Sentinella surveillance system 1986-1993. Sentinella Work Group]. / Mumps-Epidemiologie in der Schweiz: Ergebnisse der Sentinella-Uberwachung 1986-1993. Sentinella-Arbeitsgemeinschaft.

UNLABELLED: Since 1990, there have been reports of an increasing number of mumps cases in Switzerland, in particular among vaccinated children, and of local outbreaks of mumps. Using data from the Sentinella reporting system, a network of voluntary participating doctors (general practitioners, internists and paediatricians, yearly average: n = 141), trends and factors influencing mumps incidence in the general population were assessed during the last seven years. Following an initial decline in mumps reports, since 1990, there has been a continuous and marked increase in reports from a minimum of 0.7 cases per physician and year in 1989/90 to a near five-fold increase of 3.3 cases in the last reporting period from June-December 1993 (calculated for one year). Half of this increase, which is reflected in a doubling of the number of cases reported in 1986/87, is explained by an increase in cases among vaccinated children. The trend in mumps cases contrasts with that of measles and rubella, where there has been a clear decline in these reports since 1986 (approximately 70-80%). Complications were reported in 75 (4.0%) of the total number of mumps patients (n = 1894); in 2/5 of the cases this was a meningitis, in 1/3 an orchitis. Based on available data on vaccination coverage, the estimated efficacy of the mumps vaccines against parotitis is between 47-77%; this is clearly lower than the corresponding figure for measles (91-97%) and rubella (89-97%) vaccines. The relatively low efficacy against parotitis is mainly due to a protective level of 13-73% of the vaccines containing the Rubini strain. The estimated efficacy of the Rubini vaccines against complications is 50-81%; it is nearly 60-90% if a possible reporting bias is taken into consideration. CONCLUSIONS: 1. The Rubini strain vaccines, which are the most commonly used in Switzerland, seem to have played an important role in the clear increase in mumps cases since 1990. 2. The situation seems more favourable concerning the efficacy against complications of the vaccines used. 3. Our data support the high efficacy of all measles and rubella vaccines. 4. The surveillance of MMR by the Sentinella reporting system provides a useful and effective manner to evaluate the MMR vaccination programme.