Elsevier

Experimental Neurology

Volume 215, Issue 1, January 2009, Pages 167-177
Experimental Neurology

Cognitive dysfunction after experimental febrile seizures

https://doi.org/10.1016/j.expneurol.2008.10.003Get rights and content

Abstract

While the majority of children with febrile seizures have an excellent prognosis, a small percentage are later discovered to have cognitive impairment. Whether the febrile seizures produce the cognitive deficits or the febrile seizures are a marker or the result of underlying brain pathology is not clear from the clinical literature. We evaluated hippocampal and prefrontal cortex function in adult rats with a prior history of experimental febrile seizures as rat pups. All of the rat pups had MRI brain scans following the seizures. Rats subjected to experimental febrile seizures were found to have moderate deficits in working and reference memory and strategy shifting in the Morris water maze test. A possible basis for these hippocampal deficits involved abnormal firing rate and poor stability of hippocampal CA1 place cells, neurons involved in encoding and retrieval of spatial information. Additional derangements of interneuron firing in the CA1 hippocampal circuit suggested a complex network dysfunction in the rats. MRI T2 values in the hippocampus were significantly elevated in 50% of seizure-experiencing rats. Learning and memory functions of these T2-positive rats were significantly worse than those of T2-negative cohorts and of controls. We conclude that cognitive dysfunction involving the hippocampus and prefrontal cortex networks occur following experimental febrile seizures and that the MRI provides a potential biomarker for hippocampal deficits in a model of prolonged human 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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