Effects of a naturally occurring neurosteroid on GABA(A) IPSCs during development in rat hippocampal or cerebellar slices

1. The effects of the naturally occurring neurosteroid tetrahydrodeoxycorti costerone (THDOC) on GABA(A) receptor-mediated miniature, spontaneous and e voked IPSCs was tested using patch-clamp techniques in slices of hippocampu s and cerebellum from rats at two developmental stages (similar to 10 and s imilar to 20 days postnatal). The cells studied were hippocampal granule ce lls and cerebellar Purkinje and granule cells. 2. Most miniature GABAergic currents (mIPSCs) decayed with two exponentials and neurosteroids caused a similar to 4-fold increase in the decay time co nstant of the second exponential at the highest concentration used (2 mu M) . Similar effects were seen at high concentrations of THDOC (1-2 mu M) in a ll cell groups tested. No effects were seen on amplitude or rise time of mI PSCs. 3. The effects of THDOC (1 mu M) were shown to be stereoselective and rapid ly reversible, indicating that the neurosteroid binds to the GABA(A) recept or, rather than acting genomically. 4. At concentrations of THDOC likely to occur physiologically (50-100 nM), the decay time of IPSCs was also enhanced (25-50%) in all cerebellar cell g roups tested. In contrast, at 100 nM THDOC, seven of 11 hippocampal granule cells were sensitive from the 10 day group but the 20 day hippocampal gran ule cells showed no significant enhancement in the presence of these lower concentrations of THDOC. 5. The differences in sensitivity of hippocampal and cerebellar cells to TH DOC are compared to data reported in the literature on regional development of expression of different receptor subunits in the brain and it is sugges ted that the progressive relative insensitivity of the 20 day hippocampal c ells may depend on increasing expression of the delta subunit of the GABA(A ) receptor and possibly an increase in the alpha 4 subunit.