DHEAS induces short-term potentiation via the activation of a metabotropic glutamate receptor in the rat hippocampus.

The neurosteroid dehydroepiandrosterone-sulfate (DHEAS) is a positive modulator of synaptic transmission in mammalian brains; however, the underlying molecular mechanisms are not fully understood. This report describes the acute effects of DHEAS on the synaptic transmission in the hippocampal dentate gyrus of rat brain slices. The application of DHEAS for 10 min augmented the optically recorded EPSP (op-EPSP) in a dose dependent manner. The effect became visible at 1 nM and saturated at 100 nM. We focused on the effect of DHEAS at 100 nM, where the op-EPSP amplitude was increased by 30%, and gradually decreased to the basal level in 30 min after wash out of the drug (short-term potentiation by DHEAS; STP(DHEAS)). DHEAS did not alter the presynaptic properties including the presynaptic fiber volley (PSFV) and paired pulse facilitation (PPF), thus indicating that the acute DHEAS effect is of postsynaptic origin. The involvement of putative DHEAS targets, GABA(A), NMDA, and σ1 receptors in STP(DHEAS) was also investigated; however, antagonists to these receptors only partially inhibited the acute effect of DHEAS. By contrast, STP(DHEAS) was totally inhibited by either the metabotropic glutamate receptor 5 (mGluR5) antagonist MPEP (10 μM) or the ryanodine receptor (RyR) inhibitors (ryanodine and ruthenium red), but not by the mGluR1 antagonist LY367385 and the IP3R antagonist 2-APB, suggesting that STP(DHEAS) is mediated by an mGluR5-RyR cascade in postsynaptic neurons. Consistent with this finding, the selective agonist for mGluR5 CHPG nearly perfectly mimicked the DHEAS effect. This is the first demonstration of mGluR involvement in the DHEAS action in regard to hippocampal synaptic transmission.