Endogenous pregnenolone sulfate acts presynaptically in the dentate gyrus to modulate the entorhinal-hippocampal input

Pregnenolone sulfate (PregS) increases retention in hippocampal-dependent learning tasks. Neurosteroids such as dehydroepiandrosterone sulfate and pregnenolone sulfate (PregS) can be synthesized de novo within the cortex. Thus, PregS may act as an endogenous modulator of functional hippocampal pathways. The dentate gyrus plays a major role in hippocampal operation because of its function as a dynamic interface between hippocampal and other cortical circuits. It is believed that this subfield is an important filter of information flow from the entorhinal cortex to the CA fields of the hippocampus. Modulators of the delicate balance between excitation and inhibition of this region will have a dramatic impact on hippocampal-dependent learning and memory. Field excitatory postsynaptic potentials (fEPSPs), inhibitory postsynaptic currents (IPSCs), and excitatory postsynaptic currents (EPSCs) were recorded in the dentate granule cell layer of the hippocampal slice in response to perforant pathway and mossy fiber stimulation. Two steroid sulfatase inhibitors were used to measure the response to the accumulation of endogenously-produced sulfated steroids. Varied inter-pulse intervals were explored in an attempt to separate the presynaptic effects of low concentrations of PregS from its effect on postsynaptic GABA_A receptors. Population spikes were measured for various concentrations of PregS to obtain dose-response curves at both inhibitory and facilitory intervals. Measures of evoked IPSCs and EPSCs in granule cells were used to further investigate the effects observed with paired population spikes. The results presented here indicate that PregS acts presynaptically at low, physiologically relevant, concentrations to alter the excitability of granule cells. A model of dentate gyrus circuitry is proposed to explain how the presynaptic action of PregS at low concentrations may alter the filtering dynamics of this important subfield. The functional effects of this alteration were explored with stimulation of the perforant pathway at frequencies akin to the endogenous signal from the entorhinal cortex and the influence of PregS was assessed. Positive modulation by PregS at a low frequency with negative modulation at a high frequency was found. The importance of these signal modulating properties of endogenous concentrations of PregS on the circuit dynamics of the hippocampus and hippocampal-dependent learning and memory is discussed.