Cognitive dysfunction after experimental febrile seizures
Introduction
Seizures associated with fever, termed “febrile seizures” are the most common seizure variant in young children, occurring in 2–5% of individuals before age 5 years (Hauser, 1994, Huang et al., 1999a, Shinnar and Glauser, 2002). Epidemiological clinical studies suggest that most children with febrile seizures have normal development and intelligence (Annegers et al., 1987, Chang et al., 2001, Verity et al., 1998). However, some children with prolonged febrile seizures are at risk for long-term cognitive disturbances. For example, in a prospective study, Chang et al. (2001), who examined hippocampus-mediated learning and memory function in children, found that infants who had febrile seizures before the age of 1 year had deficits in this realm. These authors examined cognitive function at age 6 years in children who did not develop epilepsy after febrile seizures. Therefore, these data suggest that complex febrile seizures in themselves might affect normal neuronal function within the hippocampal circuit (Baram and Shinnar, 2001).
To investigate the effect of febrile seizures on cognitive function we employed a well established model of prolonged experimental febrile seizures (EFS) (Dube et al., 2000, Dube et al., 2006). In this model rat pups at postnatal day 10 develop generalized seizures after exposure to a stream of heated air to approximately 41 °C. The seizures occur at the age where hippocampal development is equivalent to that of human infants. These EFS: (i) are limbic in semiology and involve the hippocampal formation (Dubé et al., 2000); (ii) induce transient neuronal injury but no cell death (Toth et al., 1998, Bender et al., 2003a); (iii) cause profound and enduring alterations in the expression of several channel genes (Brewster et al., 2002, Brewster et al., 2005); (iv) enhance hippocampal excitability long-term (Dubé et al., 2000); and (v) result in spontaneous seizures and interictal epileptiform activity (Dubé et al., 2000). The model therefore mimics the human condition in many regards.
MRI scans were performed on the rats following the EFS to determine if there was evidence of brain injury. We then assessed learning and memory in the rats once they reached adulthood using both behavioral and electrophysiological techniques. We focused on “place cells”, a subset of CA1 pyramidal cells that fire preferentially at particular locations (firing fields) in the space available to the animal (O'Keefe, 1973, Muller, 1996). Action potential frequency of these place cells is high only when the head of a freely moving rat is in the cell-specific region of the space (Foster et al., 1989, Muller and Kubie, 1989). Place fields form within minutes of being placed in an environment and persist for months if the environment remains stable (Muller and Kubie, 1987, Muller et al., 1987, Thompson and Best, 1989, Thompson and Best, 1990), suggesting that hippocampal place cells encode the salient features of spatial experience. This rapid and persistent neuronal encoding is a crucial step toward the formation of long-term spatial memory (Shapiro, 2001). Thus, place cells serve as a reliable surrogate marker for assessing spatial memory (Holmes and Lenck-Santini, 2006, Zhou et al., 2007).
We report here that EFS result in impaired prefrontal and hippocampal function and that increased MRI T2 signal changes following prolonged EFS are associated with such cognitive impairment at both the behavioral and cellular level.
Section snippets
Animals and induction of EFS
Sprague–Dawley-derived rats were born and maintained in quiet facilities under controlled temperatures and light schedule. Cages were monitored every 12 h for the presence of pups and the date of birth was considered as Day 0. On postnatal day (P) 2, litters were culled to male pups. When weaned (on P21), rats were housed 2–3 per cage. Only male rats were used in the study. Experimental procedures were approved by Institutional Animal Care Committees and conformed to NIH guidelines.
EFS were
Behavioral features of EFS
The behavioral seizures of the EFS were stereotyped, consisting of a sudden arrest of heat-induced hyperkinesias, together with facial automatisms. These movements were then followed by body flexion. The behavioral seizures lasted approximately 24 min. These behavioral events have previously been shown to correlate with electrographic hippocampal seizures. None of the controls had any behavioral seizures noted.
T2 values in a subset of rats experiencing experimental prolonged febrile seizures are abnormal
MRI studies were performed a month after the EFS, a time-point when spontaneous
Discussion
The principal findings of these experiments are: (1) prolonged experimental febrile seizures are associated with impairment in hippocampal-dependent learning and memory and prefrontal cortex-dependent strategy switching when the rats are tested as adults; (2) T2 weighted MR imaging delineates two outcomes after early-life EFS: a subgroup of rats with abnormal T2 signal in hippocampus, and a second population with T2 values that do not differ significantly from those in the controls. Rats with
Acknowledgments
We thank J. Calara for expert editorial help. Supported in part by NIH grants: NS044296 (GLH), R21 NS49618 (GLH and TZB) and R37 NS35439 (TZB).
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