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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.
Recurrent seizures are the signature symptom of epilepsy. Yet, seizures are also very often observed in several “clinically distinct” childhood developmental disorders. For example, many children afflicted with autism spectrum disorders (ASD) or attention deficit hyperactivity disorder (ADHD) will experience clinical or subclinical seizures, and those that do not still harbor an increased susceptibility relative to other children (Hesdorffer et al., 2004; Deonna & Roulet, 2006). Indeed, up to 80% of females with Rett syndrome, an ASD-related developmental disorder, exhibit severe seizures. The inverse relationship is also true, whereby children newly diagnosed with various epilepsies will generally present with an elevated risk for behavioral problems and/or ADHD that is unrelated to seizure-induced neurological sequelae (Kanner, 2003). Such a high degree of clinical overlap between ASD/ADHD and epilepsy is suggestive of a common underlying pathophysiology, which may ultimately rely on particular epigenetic events to dictate the severity and exact nature of the final clinical presentation.
In support of this theory, rat strains that were naturally bred to be seizure-prone, but not those bred for seizure resistance, exhibit several comorbid behavioral features that are remarkably similar to symptoms observed in humans with ADHD/ASD. Specifically, two rat strains were selectively bred over 11 generations for fast and slow seizure development in response to repeated electrical stimulation of the amygdala (kindling) (Racine et al., 1999). These rat strains now show reliable differences in susceptibility across several seizure induction paradigms, including the chemoconvulsants kainate and pilocarpine. Thus, since the original selection process, natural breeding has sustained a population of rats that is natively seizure-prone (Fast) and another that is seizure-resistant (Slow). Importantly, as often occurs in selective breeding studies, several comorbid features have arisen in the seizure-prone, Fast strain that are decidedly reminiscent of ADHD/ASD. Relative to Slow rats, Fast rats are highly impulsive and hyperactive and display obvious learning deficits in numerous testing paradigms (Gilby et al., 2007). Age-inappropriate juvenile and aggressive play behaviors are also obvious in Fast but not in Slow rats (Reinhart et al., 2004). In addition, Fast rats will, at times, show stereotypic/repetitive behaviors such as circling their cages, compulsively moving pups around, or excessively licking themselves or offspring until the targeted area is bare. While the incidence of these repetitive behaviors is low (approximately 1 in 100 rats), it occurs reliably in all breeding rounds. Alongside these behavioral indications, Fast rats naturally exhibit relative polydipsia, polyuria, dry skin, and altered brain morphology, primarily involving the white matter and hippocampal and ventricular volumes. Finally, urinary organic acid metabolic screening has revealed reduced excretion of 3- & 4-hydroxyphenylproprionic acid (a metabolite of phenylalanine or tyrosine) in Fast rats. Interestingly, phenylethylamine (PEA), which is biosynthesized from the amino acid phenylalanine, and phenylalanine itself are known to be reduced in the urine of ADHD/ASD patients (Kusaga, 2002). Indeed, all of these traits expressed by Fast rats or some combination thereof, have been documented in ADHD/ASD patients and individuals suffering from epilepsy (Kobyashi et al., 2002; Krain & Castellanos, 2006; Richardson, 2006). The evolution of these behavioral and physical symptoms in rats naturally bred to be seizure-prone adds powerful support to the concept of a spectrum of vulnerability toward these clinically interrelated disorders. Further evidence for a common underlying pathophysiology in patients suffering from ADHD/ASD and related neurodevelopmental disorders has been eloquently reviewed by Richardson (2006).
For many years, dietary therapy involving fatty acid supplementation has been endorsed for the treatment of ADHD/ASD and epilepsy at both the clinical and the basic research levels. More recently, these therapies have been gaining ground. Strategies have ranged from the very rigid ketogenic diet (KD), designed primarily for seizure control, to tactics as simple as low-dose omega-3 supplementation of a normal diet, ultimately aimed at improving mood and behavior in patients (Greene et al., 2003; Richardson, 2006). Clearly, the success of these therapies in both animal models and patients advocates a role for nutrition, and for fatty acids more specifically, in each of these disorders. Accordingly, aberrant metabolism or lipid handling may be at the root of behavioral and physiological traits that typify the Fast rat phenotype. This hypothesis stems primarily from the observation that while Fast and Slow rats are maintained on an identical and highly optimized diet, plasma levels of nonesterified fatty acids (NEFA) in Fast rats are about half that of Slow rats. Levels for most other plasma constituents, however, are indistinguishable between these strains. Additional signs of abnormal metabolism in Fast versus Slow rats include their significantly higher resistance to carbon dioxide induced asphyxia such that Fast rats appear to have extra energy reserves with which to deal with respiratory compromise (Fig. 1). Moreover, as mentioned previously, Fast rats show physical signs of essential fatty acid (EFA) deficiency including excessive thirst, frequent urination, and dry skin, which makes them highly prone to humidity-dependent ringtail as pups. The fact that these differences occur while Fast and Slow rats are held on identical diets and in the same environment is highly suggestive of a strain-specific metabolism that is likely to involve disparities in lipid handling.
Figure 1. Male and female Fast rats survive significantly longer when exposed to carbon dioxide-induced respiratory compromise. This effect is stronger in males than in females. ★= significance at p <.01.
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Ultimately, the convergent validity of this animal model makes the seizure-prone Fast rats appear more as a homology to several aspects of the ADHD/ASD condition than an analogy. Moreover, they may well provide conclusive evidence of the recently suspected “spectrum of vulnerability” toward these interrelated disorders. These findings also suggest that Fast and Slow rats would respond very differently to dietary management, particularly to the diets generally prescribed for epilepsy and ADHD/ASD. For all of these reasons, we believe that Fast rats and their comparison strain (Slow rats) offer a new and exciting venue through which to study predisposing factors that underwrite the development of ADHD/ASD and epilepsy and should help to identify new therapeutic strategies for the treatment of these disorders.