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¹ Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA

We used Magnesium Green AM to measure Ca²⁺ transients in Schaffer collateral presynaptic terminals simultaneously with postsynaptic field potentials (fEPSPs) to investigate the mechanism of neurosteroid enhancement of short-term synaptic facilitation. Measurement of [Ca²⁺]_i, isolated to presynaptic events, using the fluorescence ratio (F/F₀) demonstrated that at a constant stimulus intensity there was no change in the excitability of presynaptic fibres between paired stimuli or between ACSF and 1 µM pregnenolone sulphate (PREGS). Paired-pulse facilitation (PPF) was correlated with residual Ca²⁺ ([Ca²⁺]_res), and there was an additional increase in the F/F₀ for the [Ca²⁺]_res-subtracted response to the second of paired stimuli, resulting primarily from a slowing of the decay time constant. In addition to the role of presynaptic [Ca²⁺]_res in PPF, we observed a decrease in EC₅₀ and a greater maximum for Hill function fits to fEPSP versus F/F₀ during the second of paired responses. The enhancement of fEPSP PPF by PREGS did not result from an increase of F/F₀. The data presented here support a PREGS-induced increase in presynaptic glutamate release from the second, but not the first, of a pair of stimuli for a given presynaptic [Ca²⁺] because: (a) there is actually a decrease in the F/F₀ of the [Ca²⁺]_res-subtracted second response over that seen in ACSF; (b) PREGS causes no change in presynaptic Ca²⁺ buffering; and (c) there is a decrease in EC₅₀ and an increase of y_max in the Hill function fits to F/F₀ versus fEPSP data. We hypothesize that PREGS enhances short-term facilitation by acting on the Ca²⁺-dependent vesicle release machinery and that this mechanism plays a role in the cognitive effects of this sulphated neurosteroid.

(Received 2 August 2006; accepted after revision 18 August 2006; first published online 24 August 2006)
Corresponding author L. D. Partridge: Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA. Email: dpartridge{at}salud.unm.edu