Pregnenolone Sulfate as a Modulator of Synaptic Plasticity

Abstract

Neurosteroids such as pregnenolone have been implicated in the pathophysiology of neuropsychiatric disorders such as schizophrenia and cannabinoid addiction (1, 2). Our laboratory discovered that the unique negatively charged steroid pregnenolone sulfate (PregS), the product of pregnenolone metabolism via a single sulfation step, modulates fast excitatory synaptic transmission by potentiating NMDA receptor activity in a fashion that is balanced by AMPA receptor inhibition at micromolar concentrations. We recently reported finding a novel high affinity response to PregS (EC50 = 2 pM) that increases intracellular [Ca2+] and CREB activation in cultured rat cortical neurons. Here, we report that PregS increases glutamate receptor and PSD95 colocalized puncta, presumably on dendritic spines of hippocampal neurons, suggesting that PregS increases surface‐postsynaptic AMPARs and NMDARs. Whole cell recordings of primary rat hippocampal neurons revealed that PregS increases the frequency of spontaneous excitatory postsynaptic currents, suggesting an increase in glutamate release from presynaptic terminals or an increase in the number of activatable synapses. The results indicate that PregS acts within the physiological range of endogenous concentrations (3) to recruit AMPA receptors to postsynaptic sites, thereby altering synaptic plasticity.(1) Marx et al. (2009) Neuropsychopharmacology 34:1885‐1903(2) Vallée et al. (2014) Science 343(6166):94‐8(3) Rustichelli et al. (2013) J Chromatogr B Analyt Technol Biomed Life Sci. 930:62‐9