The neurosteroids allopregnanolone (5α-pregnan-3α-ol-20-one; 5α,3α-P) and its 5β-epimer pregnanolone (5β,3α-P), and pregnenolone sulfate (PS) were examined for effects on spontaneous epileptiform discharges induced by 100μM picrotoxin (PTX) and 55μM 4-aminopyridine (4-AP) in the CA3 region of the rat hippocampal slice. At a concentration of 10μM, 5α,3α-P partially reduced PTX-induced bursting and at 30 and 90μM completely suppressed bursting. In contrast, 100μM 5β,3α-P failed to alter the discharge frequency. 5α,3α-P depressed 4-AP-induced bursting with similar potency as in the PTX model; 100μM 5β,3α-P was also partially effective. In the 4-AP model, 5α,3α-P inhibited both the more frequent predominantly positive-going potentials as well as the less frequent negative-going potentials that may be generated by synchronous GABAergic interneuron firing. PS enhanced the PTX bursting frequency and, in the 4-AP model, increased the frequency of negative potentials but did not alter the frequency of positive potentials. By itself, PS did not induce bursting. The effects of the steroids in the in vitro seizure models largely correspond with their activities on GABAA receptors; suppression of discharges may occur as a result of direct activation of these receptors rather than modulation of GABA-mediated synaptic responses. PTX and 4-AP-induced bursting in the hippocampal slice are useful models for directly assessing neurosteroid effects on seizure susceptibility under conditions that eliminate the factor of brain bioavailability.
- Hippocampal slice
ASJC Scopus subject areas
- Clinical Neurology
- Pediatrics, Perinatology, and Child Health