Krista L. Gilby

Mapping seizure pathways in the temporal lobe

Interest in temporal lobe seizure pathways has a long history based initially on the human condition of temporal lobe epilepsy (TLE). This interest in TLE has extended more recently into explorations of experimental models. In this review, the network structures in the temporal lobe that are recruited in animal models during various forms of limbic seizures and status epilepticus are described. Common to all of the various models is recruitment of the parahippocampal cortices, including the piriform, perirhinal, and entorhinal areas. This cortical involvement is seen in in vitro and in vivo electrophysiological recordings throughout the network, in trans‐synaptic neuroplastic changes in associated network structures manifest at the molecular level, in network energy utilization visualized by 14C 2‐deoxyglucose uptake, and finally, in the behavioral consequences of network lesions. The conclusions of the animal models reviewed here are very similar to those described for the human condition presented recently in the 2006 Lennox lecture by Warren Blume, and addressed 53 years ago in the quadrennial meeting of the ILAE in 1953 by Henri Gastaut.

Effect of Focal Low‐frequency Stimulation on Amygdala‐kindled Afterdischarge Thresholds and Seizure Profiles in Fast‐ and Slow‐kindling Rat Strains

Summary:  Purpose: To determine whether low‐frequency, 1‐Hz sine‐wave stimulation (LFS) applied to a fully kindled amygdala focus would show antiepileptic properties in rats that were either naturally seizure prone (Fast) or seizure resistant (Slow).

Genetically seizure-prone or seizure-resistant phenotypes and their associated behavioral comorbidities.

Summary  It was questioned whether amygdala kindling, a model of temporal lobe epilepsy, is under genetic control, and is associated with comorbid behavioral features. Initially, rats were selectively bred for speed of amygdala kindling, and, in subsequent generations, were assessed in behavioral paradigms to measure activity, emotionality, impulsivity, and learning. Clearly kindling was under genetic control, as two strains were developed to be either Fast or Slow to kindle, and each was associated with different neurological, electrophysiological and behavioral features. Behaviorally, the Fast rats appear much like humans with attention deficit hyperactivity disorder (ADHD), showing easy distraction, hyperactivity and impulsivity, compared to Slow rats.

Differential GABAA Subunit Expression Following Status Epilepticus in Seizure-prone and Seizure-resistant Rats: A Putative Mechanism for Refractory Drug Response

Summary:  Purpose: Two rat strains were selectively bred to be prone (Fast) or resistant (Slow) to amygdala kindling. The first objective of this experiment was to determine whether that selection was specific to kindling or was sensitive more broadly to another seizure induction agent, kainic acid (KA). Second, we investigated whether these strains exhibit distinct molecular responses to KA with respect to GABAA receptor subunit expression.

Chronic omega-3 supplementation in seizure-prone versus seizure-resistant rat strains: a cautionary tale

Several studies have shown fatty acid supplementation to be efficacious in the treatment of attention deficit hyperactivity disorder/autism spectrum disorder (ADHD/ASD) and epilepsy. Interestingly, rats bred to be seizure-prone (Fast), unlike those bred for seizure-resistance (Slow), naturally exhibit behaviors and physiology reminiscent of ADHD/ASD in humans, suggesting a fundamental link between seizure disposition and these developmental disorders. To determine whether chronic omega-3 supplementation might ameliorate ADHD-like behaviors in the seizure-prone rat strain and/or alter natural predispositions for or against seizure in either strain, Fast and Slow weanlings were maintained on a control or omega-3-supplemented diet. As adults, rats were tested in paradigms known to elicit ADHD-like behaviors from Fast rats and then kindled from the amygdala to assess relative seizure disposition. While omega-3 supplementation did not significantly alter the relative hyperactivity, learning deficits or heightened seizure sensitivity naturally exhibited by Fast rats, it dramatically reduced their impulsivity to Slow-like levels. In contrast, typical behavioral patterns in Slow rats were largely unaffected by omega-3 supplementation yet their proclivity for seizure was greatly increased. This heightened vulnerability to seizure in Slow rats was paralleled by a drop in circulating plasma non-esterified fatty acids (NEFA) to match levels normally observed in Fast rats. These findings suggest a delicate balance between seizure predisposition and ADHD-like behaviors that can be influenced by omega-3 treatment. Further, a relationship between circulating NEFA levels and seizure susceptibility has surfaced that advocates caution when treating different genetic backgrounds with omega-3 fatty acids.

Postnatal epigenetic influences on seizure susceptibility in seizure-prone versus seizure-resistant rat strains.

The creation of seizure-prone (Fast) and seizure-resistant (Slow) rat strains via selective breeding implies genetic control of relative seizure vulnerability, yet ample data also advocates an environmental contribution. To investigate potential environmental underpinnings to the differential seizure sensitivities in these strains, the authors compared amygdala kindling profiles in adult male Fast and Slow rats raised by (a) their own mother, (b) a foster mother from the same strain, or (c) a foster mother from the opposing strain. Ultimately, strain-specific kindling profiles were not normalized by cross-fostering. Instead, both strains became more seizure-prone regardless of maternal affiliation (i.e., cross-fostered groups from both strains kindled faster than uncrossed controls). Interhemispheric seizure spread was also facilitated in cross-fostered Slow rat groups and was associated with increased commissural cross-sectional areas, giving them a Fast-like profile. It is important to note, however, that all Fast groups remained significantly more seizure-prone than Slow groups, suggesting that although the postnatal environment strongly influenced seizure disposition in both strains, it did not wholly account for their relative dispositions. Investigation into mechanisms fundamental to cross-fostering-induced seizure facilitation should help prevent postnatal worsening of pathology in already seizure-prone individuals.

Ruling out postnatal origins to attention-deficit/hyperactivity disorder (ADHD)-like behaviors in a seizure-prone rat strain.

Adult Fast (seizure-prone) and Slow (seizure-resistant) kindling rat strains exhibit divergent behaviors in paradigms relevant to attention-deficit/hyperactivity disorder (ADHD) in humans. Similar dissociations in rodent behavior have been linked to disparities in early life experience, suggesting that differential maternal care or postnatal interactions may underlie these behaviors. Consequently, the authors compared maternal behavior and preweaning pup weights in these 2 strains under control and cross-fostered conditions and examined its effects on subsequent adult offspring behavior. Ultimately, several distinct maternal behaviors were apparent between the 2 strains under control conditions, and some of those behaviors were then malleable by pup condition. Yet, in spite of the resultant complex maternal patterns across groups, all offspring showed behavioral phenotypes akin to their genetic strain. Thus, a specific postnatal environment is unlikely to underwrite ADHD-like behaviors in the seizure-prone Fast rats, which implicates a genetic or prenatal origin for the ADHD phenotype.

A new rat model for vulnerability to epilepsy and autism spectrum disorders

Tremendous concern has arisen in response to the recent diagnostic outbreak of childhood developmental disorders, particularly involving attention deficit hyperactivity disorder (ADHD) and the autism spectrum disorders (ASD). Interestingly, similarities in clinical presentation across these disorders may suggest common predisposing factors. For instance, though not widely recognized, an increased predisposition toward seizure is a symptom that is very often associated with ADHD and ASD. Accordingly, a rat strain naturally bred to be seizure‐prone simultaneously developed behavioral and physical characteristics analogous to those observed in ADHD/ASD patients. These rats also show early signs of aberrant lipid handling, which is another symptom common to human patients with these disorders. As such, this rat strain could serve as an excellent model system through which to identify common pathophysiological events that constitute a“spectrum of vulnerability”toward ADHD/ASD and epilepsy.

Caloric Restriction Alters Seizure Disposition and Behavioral Profiles in Seizure-Prone (Fast) Versus Seizure-Resistant (Slow) Rats

Caloric restriction (CR), primarily known for extending life span, has proven anticonvulsant in several seizure models and antiepileptogenic in a strain of inherently seizure susceptible mice. Our animal model consisted of a seizure-prone (Fast) strain that naturally exhibits attention-deficit/hyperactivity disorder (ADHD)-like behaviors and a comparison seizure-resistant (Slow) strain; we evaluated CRs effect on the typical seizure sensitivities and behavioral profiles of each strain. Fast and Slow rats were fed ad libitum or were calorically restricted to 80% of free-feeding body weight. Rats were then tested in the open field (hyperactivity), Morris water maze (learning and attention), and restraint (impulsivity) paradigms and finally kindled from the amygdala. Ultimately, CR abolished signs of abnormal hyperactivity in the Fast strain and retarded their kindling rates, making it the first manipulation to demonstrate an antiepileptogenic effect in this animal model. CR also shortened seizure durations in fully kindled Slow rats but had no effect on their kindling rates, implying a differential effect of CR on genotype. These results clearly endorse further investigation into the potential benefits of CR for both epilepsy and ADHD.

Neurodevelopment in Seizure-prone and Seizure-resistant Rat Strains: Recognizing Conflicts in Management

Summary:  Cytoarchitectural alterations during central nervous system (CNS) development are believed to underlie aberrations in brain morphology that lead to epilepsy. We have recently reported marked reductions in hippocampal and white matter volumes along with relative ventriculomegaly in a rat strain bred to be seizure‐prone (FAST) compared to a strain bred to be seizure‐resistant (SLOW) ( Gilby et al., 2002 , American Epilepsy Society 56th Annual Meeting). This study was designed to investigate deviations in gene expression during late‐phase embryogenesis within the brains of FAST and SLOW rats. In this way, we hoped to identify molecular mechanisms operating differentially during neurodevelopment that might ultimately create the observed differences in brain morphology and/or seizure susceptibility. Using Superarray technology, we compared the expression level of 112 genes, known to play a role in neurodevelopment, within whole brains of embryonic day 21 (E21) FAST and SLOW rats. Results revealed that while most genes investigated showed near equivalent expression levels, both Apolipoprotein E (APOE) and the β2 subunit of the voltage‐gated sodium channel (SCN2β) were significantly underexpressed in brains of the seizure‐prone embryos. Currently, these transcripts have no known interactions during embryogenesis; however, they have both been independently linked to seizure disposition and/or neurodevelopmental aberrations leading to epilepsy. Thus, alterations in the timing and/or degree of expression for APOE and SCN2β may be important to developmental cascades that ultimately give rise to the differing brain morphologies, behaviors, and/or seizure vulnerabilities that characterize these strains.