The GAERS or Genetic Absence Epilepsy Rat from Strasbourg is a recognized animal model of

absence epilepsy Absence seizures are one of several kinds of generalized seizures. These seizures are sometimes referred to as petit mal seizures (from the French for "little illness", a term dated in the late 18th century). Absence seizures are characterized by ...

, a typical childhood form of

epilepsy Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical ...

characterized by recurrent loss of contact and concomitant pattern on the electroencephalogram called "spike-and-wave" discharges. It was first characterized in

Strasbourg Strasbourg (, , ; german: Straßburg ; gsw, label=Bas Rhin Alsatian, Strossburi , gsw, label=Haut Rhin Alsatian, Strossburig ) is the prefecture and largest city of the Grand Est region of eastern France and the official seat of the Eu ...

in the 1980s and since then has been used by different international research groups to understand the mechanisms underlying absence seizures and their

ontogeny Ontogeny (also ontogenesis) is the origination and development of an organism (both physical and psychological, e.g., moral development), usually from the time of fertilization of the egg to adult. The term can also be used to refer to the stu ...

, using different techniques.

History

In the 1980s the research group of Marguerite Vergnes at Institut National de la Santé et de la Recherche Médicale ( INSERM) in Strasbourg (France) reported the spontaneous occurrence of

spike-and-wave Spike-and-wave is a pattern of the electroencephalogram (EEG) typically observed during epileptic seizures. A spike-and-wave discharge is a regular, symmetrical, generalized EEG pattern seen particularly during absence epilepsy, also known as ‘p ...

discharges (SWD) evocative of absence seizures in Wistar rats during cortical

electroencephalographic Electroencephalography (EEG) is a method to record an electrogram of the spontaneous electrical activity of the brain. The biosignals detected by EEG have been shown to represent the postsynaptic potentials of pyramidal neurons in the neocortex ...

(EE]) recordings. These seizures were recorded on both sides of the brain, lasted about 20 sec and occurred when the animals were quiet. Importantly, SWD were always associated with a typical "arrest" of the rats' behavior with twitching of the vibrissae. In addition, drugs used in the clinic to stop absence seizures (ethosuccimide,

valproate Valproate (VPA) and its valproic acid, sodium valproate, and valproate semisodium forms are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches. They are useful for the prevention of seizures in those ...

) suppressed SWDs in these rats, whereas those that aggravate these seizures in patients (

carbamazepine Carbamazepine (CBZ), sold under the trade name Tegretol among others, is an anticonvulsant medication used primarily in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other medi ...

, phenytoine), increased rats' seizures.

Development of two strains

These initial observations led to the development of two breeding colonies: (i) a fully inbred strain of rats, with 100% of animals displaying the EEG and behavioral characteristics of absence seizures, derived from an outbred Wistar colony and called the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) (ii) a strain of non epileptic control animals selected from the same initial breeding colony of Wistar rats and called the NEC. Since then, the GAERS has been recognized as a very predictive model for

, along with the WAG/Rij rat model. The colony, initially developed in Strasbourg (France), is maintained at the University of Grenoble Alpes (France) under Inserm licence.

Effects of antiepileptic drugs

The reactivity of GAERS to antiepileptic drugs is unique since it perfectly matches with the effects of these drugs in patients with typical absence epilepsy The following table summarizes the effects of the different antiepileptic that were tested on GAERS:

Genetic transmission and chromosomal mapping

In GAERS x NEC F1 generation, more than 95% of the animals showed SWDs after 6 months, suggesting a dominant transmission. Similar SWDs were recorded in males and females, indicating that the transmission is autosomal. Inter-individual variability suggested that the inheritance of SWDs is not due to a single gene locus and/or that environmental effects might play a role. This mode of inheritance was confirmed in F2 (F1 x F1) and backcross (F1 x control) generations. When F2 population was generated by breeding GAERS with Brown Norway rats, a polygenic inheritance of SWD-related phenotypes was shown and three quantitative trait loci were identified that could control different variables of SWDs (e.g., frequency, amplitude, duration). In this study, the age of the animals was found to be a major factor influencing the detection of genetic linkage to the various components of the SWDs. The development of two inbred strains from the same initial colony has appeared as a very powerful tool to study the possible mutations involved in a genetically complex idiopathic epilepsy. A functional mutation in the ''Cacna1h'' gene encoding the Cav3.2 low-voltage activated Ca2+ channel was found using the two strains. In addition, the effect is due to a gain-of-function splice variant mutation, and is semi-dominant, explaining about 20% of the phenotypic variance in the cross. In heterologous expression studies, it was shown that the GAERS splice variant allele on Cav3.2 conferred faster recovery from channel inactivation and greater charge transference during high-frequency bursts. This is in agreement with a previous study that showed a selective increase in the T-type conductance in GAERS nRT neurons. It is also in line with the role of the low voltage activated Ca2+ channel in thalamic burst firing and genetic data in human patients.Hughes, J.R., 2009. Epilepsy & Behavior. 15, 404–412.

References

{{Reflist Electroencephalography