A tale of two rodents: exploring the mechanisms of natural seizure resistance

In my lab’s weekly lab meeting, a Brazilian post-doctoral researcher, Leo Faria presented a research article entitled Distinctive Hippocampal CA2 subfield of the Amazon Rodent Proechimys. This particular rodent, the Guyenne Spiny rat, is an example about how natural evolution might produce unique examples of adaptation that are ideal substrates for advancing basic knowledge of brain function.

Proechymis Guyanensis (The Guyenne Spiny rat) is native to the Amazon basin, found in parts of Brazil, Colombia, French Guyana, Guyana, Surinam and Venezuela. It is a member of the spiny rat group of rodents, which are closely related to guinea pigs and chinchillas, though they more resemble rats. Like other members of the Echimyidae family, spiny rats can break off their tails when attacked (though their tails do not regenerate). Members of the spiny rat family can be terrestrial (living on land), arboreal (living in trees) or fossorial (living underground), with almost all members herbivorous.

Why are the Guyenne Spiny rats interesting to a neuroscientist? For the simple reason that they appear resistant to most of the common models of inducible epilepsy.

Some background: epilepsy is a neurological disorder that affects approximately 50 million people worldwide and is characterized by recurrent seizures (1). The exact mechanisms underlying the development of epilepsy (epileptogenesis) are still an area of intense research, but several pathophysiological causes have been identified, including traumatic brain injuries and several genetic mutations. Research laboratories that study epilepsy commonly use chemical induction protocols, wherein a chemical is introduced to a rodent brain that can induce epileptogenesis. A particular flavor of epileptic seizure is termed status epilepticus, which is characterized by the development of a persistent seizure lasting longer than 30 minutes, and in human patients represents 10-20% of all first seizures (2). Chemical induction of status epilepticus within the laboratory can result in later development of chronic epilepsy in rodent models. Within a laboratory setting the injection of either Pilocarpine (a non-selective agonist of the cholinergic muscarinic receptor) or kainate (an agonist of an ionotrophic glutamate receptor) will induce status epilepticus and lead to the development of spontaneous chronic seizures. Both pilocarpine and kainate administration are used to model the pathogenesis of a particularly common form of epilepsy, temporal lobe epilepsy.

Pilocarpine and kainate injection are both well-tested methods of inducing epilepsy in rodents; however, the Guyenne Spiny-rats are completely resistant. Following injection of either of these substances, the spiny rats will fail to experience status epilepticus and will not go on to develop chronic epilepsy. The exact cellular mechanisms allowing this remarkable insensitivity are currently unknown. The research article presented during lab meeting looked at morphological differences between the brains of the Spiny rats and the more common research animal, the Wistar rat. The researchers found distinctive differences in the hippocampal CA2 subfield (which has been recently implicated in seizure generation), with the spiny rats displaying greater neuronal disorganization, larger regional size, as well as several other differences in the density of specific neuronal subtypes.

How does this difference cause resistance to epileptogenesis in the spiny rats? One hypothesis presented in the research article is that increased density of inhibitory neurons within the hippocampus might prevent the development of hyper-excitation. Unfortunately, the paper was not able to make any definitive conclusions regarding the exact mechanisms underlying seizure resistance in Spiny rats. A curious point brought up by Leo during my lab meeting was that the natural habitat of the spiny rats overlaps with the habitat of Pilocarpus jaborandi, the plant from which Pilocarpine is derived.

Have the Guyenne Spiny rats developed their seizure resistance in response to natural selection pressures established by the presence of a plant with pro-seizure properties? It’s possible. What is certain is that these animals have the potential to advance knowledge of how specific brain areas contribute to pathological epileptogenesis, as well as informing research into the prevention and treatment of a tragically debilitating neuronal disorder.