Elsevier

Neuroscience

Volume 89, Issue 3, March 1999, Pages 717-729
Neuroscience

Recurrent seizures and hippocampal sclerosis following intrahippocampal kainate injection in adult mice: electroencephalography, histopathology and synaptic reorganization similar to mesial temporal lobe epilepsy

https://doi.org/10.1016/S0306-4522(98)00401-1Get rights and content

Abstract

Human mesial temporal lobe epilepsy is characterized by hippocampal seizures associated with pyramidal cell loss in the hippocampus and dispersion of dentate gyrus granule cells. A similar histological pattern was recently described in a model of extensive neuroplasticity in adult mice after injection of kainate into the dorsal hippocampus [Suzuki et al. (1995) Neuroscience 64, 665–674]. The aim of the present study was to determine whether (i) recurrent seizures develop in mice after intrahippocampal injection of kainate, and (ii) the electroencephalographic, histopathological and behavioural changes in such mice are similar to those in human mesial temporal lobe epilepsy. Adult mice receiving a unilateral injection of kainate (0.2 μg; 50 nl) or saline into the dorsal hippocampus displayed recurrent paroxysmal discharges on the electroencephalographic recordings associated with immobility, staring and, occasionally, clonic components. These seizures started immediately after kainate injection and recurred for up to eight months. Epileptiform activities occurred most often during sleep but occasionally while awake. The pattern of seizures did not change over time nor did they secondarily generalize. Glucose metabolic changes assessed by [14C]2-deoxyglucose autoradiography were restricted to the ipsilateral hippocampus for 30 days, but had spread to the thalamus by 120 days after kainate. Ipsilateral cell loss was prominent in hippocampal pyramidal cells and hilar neurons. An unusual pattern of progressive enlargement of the dentate gyrus was observed with a marked radial dispersion of the granule cells associated with reactive astrocytes. Mossy fibre sprouting occurred both in the supragranular molecular layer and infrapyramidal stratum oriens layer of CA3. The expression of the embryonic form of the neural cell adhesion molecule coincided over time with granule cell dispersion.

Our data describe the first histological, electrophysiological and behavioural evidence suggesting that discrete excitotoxic lesions of the hippocampus in mice can be used as an isomorphic model of mesial temporal lobe epilepsy.

Section snippets

Animals and surgical procedures

Experiments were performed on 83 adult male Swiss mice (CERJ, Le-Genest-St-Isle, France) weighing about 30–35 g housed in a 12 h light–dark controlled cycle with free access to food and water. All experiments were performed in accordance to the European Committee Council Directive of November 24, 1986 (86/69/EEC). Fifty-three mice were stereotaxically injected with kainate and 30 with saline into the right dorsal hippocampus (coordinates from bregma: A=−1.8 mm and L=−1.6 mm, from brain surface:

Electroencephalographic and behavioural consequences of intrahippocampal kainate injection

Saline injection did not induce any change in EEG patterns. Following kainate administration and during awakening from surgery, the mice were immobile most of the time and presented intermittent contraversive clonic deviations of the head and chewing. Some mice displayed rotations contraversive to the site of kainate injection. EEG recordings revealed continuous or subcontinuous 2–5 Hz polyspike-and-waves in the ipsilateral cortex (Fig. 1B). This phase lasted for up to 5 h. Clonic deviations of

Discussion

Our findings provide evidence suggesting that the long-term EEG, behavioural, metabolic and histological consequences of intrahippocampal injection of kainate in mice are very similar to human MTLE.

Conclusions

Intrahippocampal kainate injection in adult mice appears to be a promising new model of human MTLE. The validity of this model relies on several behavioural and pathological features. In particular, the histological sequelae are similar to the hippocampal sclerosis described in human MTLE, particularly cell loss in the hilus and hippocampal neuronal cell layers including the more vulnerable site CA1, granule cell dispersion, astrogliosis and mossy fibre sprouting. Likewise, recurrent partial

Acknowledgements

The authors wish to thank Jean-Marc Fritschy for helpful comments. V.B. was the recipient of a grant from LAFON Laboratories and the French Collège des Enseignants de Neurologie.

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    Present address: Laboratoire de Neurobiologie et Neuro-imagerie Expérimentales, Université Victor Ségalen, Bordeaux, France.

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