Modulation of presynaptic GABAA receptors by endogenous neurosteroids

BACKGROUND AND PURPOSE Although 3 alpha-hydroxy, 5 alpha-reduced pregnane steroids, such as allopregnanolone (AlloP) and tetrahydrodeoxycorticosterone, are endogenous positive modulators of postsynaptic GABA(A) receptors, the functional roles of endogenous neurosteroids in synaptic transmission are still largely unknown. EXPERIMENTAL APPROACH In this study, the effect of AlloP on spontaneous glutamate release was examined in mechanically isolated dentate gyrus hilar neurons by use of the conventional whole-cell patch-clamp technique. KEY RESULTS AlloP increased the frequency of glutamatergic spontaneous excitatory postsynaptic currents (sEPSCs) in a dose-dependent manner. The AlloP-induced increase in sEPSC frequency was completely blocked by a non-competitive GABA(A) receptor blocker, tetrodotoxin or Cd2+, suggesting that AlloP acts on presynaptic GABA(A) receptors to depolarize presynaptic nerve terminals to increase the probability of spontaneous glutamate release. On the other hand, gamma-cyclodextrin (gamma-CD) significantly decreased the basal frequency of sEPSCs. However, gamma-CD failed to decrease the basal frequency of sEPSCs in the presence of a non-competitive GABA(A) receptor antagonist or tetrodotoxin. In addition, gamma-CD failed to decrease the basal frequency of sEPSCs after blocking the synthesis of endogenous 5 alpha-reduced pregnane steroids. Furthermore, gamma-CD decreased the extent of muscimol-induced increase in sEPSC frequency, suggesting that endogenous neurosteroids can directly activate and/or potentiate presynaptic GABA(A) receptors to affect spontaneous glutamate release onto hilar neurons. CONCLUSIONS AND IMPLICATIONS The modulation of presynaptic GABA(A) receptors by endogenous neurosteroids might affect the excitability of the dentate gyrus-hilus-CA3 network, and thus contribute, at least in part, to some pathological conditions, such as catamenial epilepsy and premenstrual dysphoric disorder.