In line with previous studies in TLE rats (Persinger et al., 1993; Stafstrom et al., 1993; Letty et al., 1995; Persinger & Koren, 1998; Stewart & Leung, 2003; Detour et al., 2005; dos Santos et al., 2005; Frisch et al., 2007; Lenck-Santini & Holmes, 2008; Inostroza et al., 2011; Langer et al., 2011), we report here that DZP-TLE rats display widespread temporal lesions associated with severe behavioral impairments. These affected basal activity, anxiety, spatial memory, and procedural memory, as reported here for the first time. As shown by Francois et al. (2011) in carisbamate-treated rats starting 1 h after SE onset, CRS-TLE rats exhibited slight neuroprotection, developed motor seizures with behavioral impairments as dramatic as DZP-TLE rats, and CRS-ALE rats with large neuroprotection developed absence-like epilepsy translating into behavioral preservation.
CRS-TLE and CRS-ALE rats
Altogether, behavioral performance of TLE rats, whether treated or not with carisbamate, was impaired to the same extent. In CRS-TLE rats, neuroprotection was limited compared to CRS-ALE rats, did not prevent the occurrence of TLE, and was insufficient to influence behavioral deficits.
The behavioral performance of CRS-ALE rats was remarkably similar to that of controls, in terms of anxiety, working, long-term spatial, and procedural memory. This preservation could result from large neuroprotection induced by carisbamate and/or from epilepsy type, absence-like instead of temporal lobe seizures. The protection provided by carisbamate in amygdala and ventral hippocampus could participate in prevention of anxiety changes occurring in TLE rats (Davis, 1992; McHugh et al., 2004; Trent & Menard, 2010). Dorsal hippocampus and entorhinal cortex were also protected, potentially contributing to learning scores and memory systems normalization (Morris et al., 1986; Dudchenko, 2004).
In CRS-ALE rats, the main features of absence epilepsy are present, that is, thalamocortical SWDs and response to clinically effective antiepileptic drugs (Francois et al., 2011). The main differences between CRS-ALE rats and genetic models of absence epilepsy are lesions in limbic regions of CRS-ALE rats. Such lesions are not found in genetic models or human absence epilepsy (Niedermeyer, 1996; Danober et al., 1998; Berg et al., 2010). Potential impact of absence epilepsy on behavior has been studied in two genetic strains of absence epilepsy, the Genetic Absence Epilepsy Rat from Strasbourg (GAERS) and the WAG/Rij. Compared to nonepileptic rats, GAERS and/or WAG/Rij rats showed no difference in spontaneous locomotor activity, feeding, social interactions, and avoidance learning, but decreased sucrose consumption, higher anxiety, increased immobility in a forced-swim test, and reduced long-term memory were noted (Coenen et al., 1991; Vergnes et al., 1991; Jones et al., 2008; Sarkisova & van Luijtelaar, 2011).
The limbic system is involved in SWD occurrence. Blood oxygen level–dependent magnetic resonance imaging in WAG/Rij rats (Nersesyan et al., 2004) and cerebral glucose utilization rates in GAERS (Nehlig et al., 1991) increase in thalamocortical structures expressing SWDs but also limbic regions and basal ganglia. Likewise, in childhood absence epilepsy, functional activity increases were recorded in all brain areas (Engel et al., 1985; Ochs et al., 1987). This indicates full participation of limbic regions in absence seizures and interdependence of temporal lobe and thalamocortical structures. The lesions remaining in some limbic regions of CRS-ALE rats (CA3, hilus, piriform, and entorhinal cortex) are likely indicative of functional changes within the limbic system that might no longer regulate the thalamocortical system, allowing the thalamocortical SWDs expression (Onat et al., 2013).
In conclusion, the current study confirms the profound deficits found in rats developing TLE. It also extends previous findings to procedural memory, affected to a dramatic extent. Despite slight neuroprotection, the behavior of TLE-CRS rats was as dramatically impaired as that of DZP-TLE rats. Finally, in CRS-ALE rats, behavioral functions were entirely preserved. These changes resulted from both insult and disease modification. It would be of interest to study further this compound with different patterns of administration to discriminate between the respective effect of insult and epileptogenesis modification and open new avenues in the search of antiepileptogenic compounds.