The role of pregnenolone sulfate in modulating neuronal excitability

Abstract

The central nervous system operates through a tightly balanced relationship of excitatory and inhibitory synaptic transmission. Neurosteroids, synthesized de novo from cholesterol in the human brain as well as converted from precursors circulating in the blood, are proven modulators of this synaptic activity. Pregnenolone sulfate, one of the most abundant endogenous neurosteroids, is a negative modulator of the GABA receptor and positive modulator of NMDA and AMPA receptors, increasing the frequency of excitatory transmission in the brain. Here, we show that low concentrations (50pM) of pregnenolone sulfate increase receptor trafficking in cultured rat hippocampal and cortical cells. Immunocytochemistry data shows that a ten-minute treatment with 50pM PS increases NR2B subunit protein. Preliminary surface biotinylation results highlight a potential increase in NR1 subunit protein. Since NMDA receptors play a pivotal role in learning and memory and have been implicated in neuropsychiatric disorder, an endogenous positive modulator of NMDA receptors is likely to play a major pharmaceutical role in neurodegenerative and memory disorders.