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

Abstract

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 (3α,5α‐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 (3α,5α‐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 3α,5α‐TH PROG remained high whereas that of 3α,5α‐TH DOC had increased, the cerebrocortical levels of both 3α,5α‐TH PROG and 3α,5α‐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 3α,5α‐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.

Absence epileptic activity changing effects of non-adenosine nucleoside inosine, guanosine and uridine in Wistar Albino Glaxo Rijswijk rats

“…For instance, it was revealed that (i) Ino showed an anticonvulsant effect on quinolinic acid (QA)-induced seizures (Ganzella et al, 2011), (ii) Guo may decrease QAinduced seizures dose-dependently (Schmidt et al, 2000) and (iii) Urd decreased epileptic activity in the rat hippocampal kindling model (Zhao et al, 2008) and in a model of human absence epilepsy Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats (Kova´cs et al, 2013b) suggesting the antiepileptic potential of non-Ado nucleosides. It is well known that GABAergic system (e.g., GABA A type of gamma-aminobutyric acid receptors: GABA A receptors), glutamatergic system (e.g., via glutamate-evoked excess hyperexcitability) and adenosinergic system (e.g., A 2A type of Ado receptors, A 2A receptors) are involved in the pathomechanisms of absence epilepsy (Snead, 1995;Coenen and Van Luijtelaar, 2003;Pisu et al, 2008;D'Alimonte et al, 2009). Thus, we hypothesized that (i) Ino and Urd may have effects on absence epilepsy through GABA A and Ado receptors (Skolnick et al, 1979;Kimura et al, 2001a;Hasko´et al, 2004;Kova´cs et al, 2015), (ii) Guo may change absence epileptic activity via the glutamatergic system De Oliveira et al, 2004;Schmidt et al, 2007;Kova´cs et al, 2015), (iii) Ino and Guo may modulate absence epilepsy through Ado receptors indirectly by their degradation to Ado or by stimulation of Ado release (Guo) (Zimmermann, 1996;Ciccarelli et al, 2000;Ipata, 2011;Kova´cs et al, 2015) and, theoretically, (iv) Guo and Urd may exert their effects on absence epileptic activity via own putative receptors (Kimura et al, 2001a(Kimura et al, , 2001bTraversa et al, 2003;Volpini et al, 2011;Kova´cs et al, 2015).…”

Upholding WAG/Rij rats as a model of absence epileptogenesis: Hidden mechanisms and a new theory on seizure development

“…Both α 4 and δ subunits are found in extrasynaptic GABA A receptors, where they facilitate tonic inhibition. Therefore, it has been hypothesized that the age-dependent increase in α 4 and δ subunits increases tonic inhibition in thalamic relay neurons, which then contributes to the age-dependent increase in SWDs (Pisu et al, 2008). GABAergic neurotransmission clearly plays a relevant role during SWDs; in WAG/Rij rats, this neurotransmitter system is functionally altered in several areas and this may depend on an altered subunit composition of GABA receptors.…”

“…Decreased allopregnanolone and 3α,5α-TH-DOC in the cortex (Pisu et al, 2008) Increase in α 4 GABA A receptor subunit expression in some dorsal thalamic nuclei and an age-dependent increase in δ subunits…”

Are Alterations in Transmitter Receptor and Ion Channel Expression Responsible for Epilepsies?

“…However, in WAG/Rij rats confl icting results have been reported. An increase in the expression of α4 and δ subunits of the GABA A receptor was observed in the relay nuclei of adult epileptic WAG/Rij animals [ 70 ] whereas decreased immunoreactivity of α3 subunit of the GABA A receptor was reported at inhibitory synapses in the reticular nucleus of the thalamus [ 47 ].…”