Animal models of absence epilepsies: What do they model and do sex and sex hormones matter?

Abstract

While epidemiological data suggest a female prevalence in human childhood- and adolescence-onset typical absence epilepsy syndromes, the sex difference is less clear in adult-onset syndromes. In addition, although there are more females than males diagnosed with typical absence epilepsy syndromes, there is a paucity of studies on sex differences in seizure frequency and semiology in patients diagnosed with any absence epilepsy syndrome. Moreover, it is unknown if there are sex differences in the prevalence or expression of atypical absence epilepsy syndromes. Surprisingly, most studies of animal models of absence epilepsy either did not investigate sex differences, or failed to find sex-dependent effects. However, various rodent models for atypical syndromes such as the AY9944 model (prepubertal females show a higher incidence than prepubertal males), BN model also with a higher prevalence in males and the Gabra1 deletion mouse in the C57BL/6J strain offer unique possibilities for the investigation of the mechanisms involved in sex differences. Although the mechanistic bases for the sex differences in humans or these three models are not yet known, studies of the effects of sex hormones on seizures have offered some possibilities. The sex hormones progesterone, estradiol and testosterone exert diametrically opposite effects in genetic absence epilepsy and pharmacologically-evoked convulsive types of epilepsy models. In addition, acute pharmacological effects of progesterone on absence seizures during proestrus are opposite to those seen during pregnancy. 17β-Estradiol has anti-absence seizure effects, but it is only active in atypical absence models. It is speculated that the pro-absence action of progesterone, and perhaps also the delayed pro-absence action of testosterone, are mediated through the neurosteroid allopregnanolone and its structural and functional homolog, androstanediol. These two steroids increase extrasynaptic thalamic tonic GABAergic inhibition by selectively targeting neurosteroid-selective subunits of GABAA receptors (GABAARs). Neurosteroids also modulate the expression of GABAAR containing the γ2, α4, and δ subunits. It is hypothesized that differences in subunit expression during pregnancy and ovarian cycle contribute to the opposite effects of progesterone in these two hormonal states.

Cerebellar output controls generalized spike‐and‐wave discharge occurrence

“…We found no significant differences in GSWD occurrence ( t 24  = −0.002, p  = 0.998) and GSWD duration ( t 24  = 0.195, p  = 0.847) between male and female tg mice, which is in line with data from other experimental animal models of absence epilepsy (reviewed by van Luijtelaar et al44). Therefore, we grouped data of both genders.…”

Extrasynaptic γ‐aminobutyric acid type A receptor–mediated sex differences in the antiseizure activity of neurosteroids in status epilepticus and complex partial seizures

“…Alternatively, testosterone‐derived estrogens may possibly dampen the protective effect of AD in males, and thereby reduce its potency. In addition, it is likely that AD and AP might also increase absence seizures in genetic absence models, most likely via their actions at δGABA‐A receptors in the thalamus …”

Antidepressants but not antipsychotics have antiepileptogenic effects with limited effects on comorbid depressive‐like behaviour in the WAG/Rij rat model of absence epilepsy

“…Finally, WAG/Rij rats have been recently indicated as a relevant animal model of genetically determined epileptogenesis (Blumenfeld et al ., ; Russo et al ., 2011a; 2013b). More specifically, WAG/Rij rats, as well as genetic absence epilepsy rats from Strasbourg (GAERS), are genetically prone to develop spontaneous absence seizures during their lifespan with only few early immature SWDs appearing on the EEG (WAG/Rij rats after P50 and GAERS probably earlier), which increase in number and duration with ageing also changing their morphology to become fully matured and expressed in all rats of the strain only after 2–3 months of age (van Luijtelaar et al ., 2011; 2014; Dezsi et al ., ). In this light, both strains of rats can be considered models of epileptogenesis where an early intervention can modify the underlying process and the future development of the genetically determined phenotype (Blumenfeld et al ., ; Giblin and Blumenfeld, ; Pitkanen and Engel, ; White and Loscher, ).…”