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Summary: Purpose: In temporal lobe epilepsy (TLE), interictal behavioral disorders affect patients' quality of life. Therefore we studied long-term behavioral impairments in the lithium-pilocarpine (li-pilo) model of TLE.
Methods: Eleven li-pilo adult rats exhibiting spontaneous recurrent seizures (SRSs) during 5 months were compared with 11 li-saline rats. Spatial working memory was tested in a radial arm maze (RAM), anxiety in an elevated plus-maze (EPM), and nonspatial working memory in an object-recognition paradigm. Neuronal loss was assessed on thionine brain sections after behavioral testing.
Results: In the RAM, the time to complete each session and the number of errors per session decreased over a 5-day period in li-saline rats but remained constant and significantly higher in li-pilo rats. In the EPM, the number of entries in and time spent on open arms were significantly higher in li-pilo than li-saline rats. In the object-recognition task, the two groups exhibited a comparable novelty preference for the new object. Neuronal loss reached 47–90% in hilus, CA1, amygdala, and piriform and entorhinal cortex.
Conclusions: In li-pilo rats having experienced SRS for 5 months, performance in the object-recognition task is spared, which suggests that object discrimination remains relatively intact despite extensive damage. Neuronal loss in regions mediating memory and anxiety, such as hippocampus, entorhinal cortex, and amygdala, may relate to impaired spatial orientation and decreased anxiety.
It is generally agreed that patients with temporal lobe epilepsy (TLE) are more prone to behavioral disorders and cognitive impairments than is the general population (1). These interictal impairments usually disrupt the patient's everyday life, often more than the seizures themselves (2,3). Furthermore, depression or anxiety often develops several years after epilepsy onset (2,4), and the control of the seizures with pharmacologic treatment does not always suppress these disorders (5). Among cognitive impairments, memory problems are frequently observed in patients with TLE. The most reliable observations are deficits in declarative memory (ability to acquire facts and events related to one's personal past, 6) and in the performance of visuospatial tasks (7–9). Moreover, long duration of refractory TLE seems to be associated with cognitive deterioration (10–12). Thus understanding the neural mechanism underlying these disturbances is an important issue in the management of TLE. In animal models of TLE, the molecular, lesional, and metabolic characteristics have been quite extensively studied. Conversely, the cognitive or behavioral validity of the models was less studied, especially after a long-lasting period of spontaneous seizures.
The model of epilepsy induced in rats by pilocarpine alone or associated with lithium reproduces most clinical and neuropathologic features of human TLE (13–17). In adult rats, the injection of lithium and pilocarpine (li-pilo) leads to status epilepticus (SE) followed by a latent seizure-free period of a mean duration of ∼3 weeks, after which all animals exhibit spontaneous recurrent seizures (SRSs) that last for their whole life (chronic period). During the latent period, neuronal loss, mossy fiber sprouting, gliosis, and synaptic reorganization participate in the constitution of a hyperexcitable circuit that underlies the occurrence of SRSs. Neuronal loss is located mainly in hippocampus, parahippocampal cortices, amygdala, and thalamus. Most of these structures are involved in behaviors like memory and anxiety (18,19). The behavioral consequences of TLE cannot be solved by the traditional approach that usually disrupts one or two regions of interest at the most. However, the lesions induced by li-pilo SE that represent multifocal brain damage resembling the neuropathology of human TLE can be used as an adequate tool for the understanding of interictal behavioral disorders in patients with TLE (17).
Previous studies on the behavioral consequences of SRSs consecutive to pilocarpine- or kainate-induced SE have concentrated mostly on memory. Thus working memory appears impaired in the Morris water maze during the latent period (20), and spatial working memory assessed in a radial arm maze is impaired during the chronic period (17,21–24). In the present work, we evaluated the long-term behavioral consequences of li-pilo SE induced in adult rats. The main difference with previous studies is that behavioral performance was assessed after a quite long period of epilepsy (i.e., 5 months of SRSs). To evaluate spatial working memory, we used the eight-arm maze (25). Deleterious effects of hippocampal lesions in learning and spatial memory have been reported in this task (18,26,27). We also used two other tasks that involve behaviors mediated by structures quite vulnerable to li-pilo SE, like the parahippocampal cortices or amygdala: the elevated-plus maze and an object-recognition task. The elevated-plus maze is designed to assess the level of anxiety in rodents (28), which depends partly on the amygdala (19). The last test was a nonspatial object-recognition task. Recognition memory is generally regarded as the ability to discriminate the familiarity of things previously encountered (29), which is critical for everyday life. This behavior, which seems to depend mostly on structures outside of the hippocampus, mainly perirhinal and entorhinal cortices (for review, see refs. 29 and 30), has never been explored in the li-pilo model. In addition, the extent of neuronal loss was assessed in the regions of interest of the same rats.