Neuroactive steroids and GABAA receptor plasticity in the brain of the WAG/Rij rat, a model of absence epilepsy

The role of neuroactive steroids and GABAA receptors in the generation of spontaneous spike-and-wave discharges (SWDs) was investigated in the WAG/Rij rat model of absence epilepsy. The plasma, cerebrocortical, and thalamic concentrations of the progesterone metabolite 3α-hydroxy-5α-pregnan-20-one (3,5-TH PROG) were increased in the WAG/Rij rat at 2 months of age compared with those in control (Wistar) rats. In contrast, the brain and peripheral levels of 3α,5α-tetrahydrodeoxycorticosterone (3,5-TH DOC) did not differ between the two rat strains at this age. At 6 months of age, when absence epilepsy worsens in WAG/Rij rats, the plasma concentration of 3,5-TH PROG remained high whereas that of 3,5-TH DOC had increased, the cerebrocortical levels of both 3,5-TH PROG and 3,5-TH DOC had increased, and the thalamic concentrations of these metabolites had decreased. At 6 months of age the expression of the α4 and δ subunits of the GABAA receptor in relay nuclei was increased. Finally, chronic stress induced by social isolation elicited a reduction in the amount of 3,5-TH PROG in the thalamus of 2-month-old WAG/Rij rats that was associated with a reduction in the number and overall duration of SWDs at 6 months of age. Absence epilepsy in the WAG/Rij rat is thus associated with changes in the abundance of neuroactive steroids and in the expression of specific GABAA receptor subunits in the thalamus, a brain area key to the pathophysiology of this condition