The function of NMDARs is regulated by a number of endogenous allosteric modulators, including membrane cholesterol and its metabolites, and endogenous neurosteroids. Although the physiological role of NMDAR-modulating sterols and steroids is not well understood, they may influence brain development and cognitive function.
We have described a number of synthetic neurosteroid analogues with either inhibitory or potentiating effects on NMDARs. Thanks to this research, neurosteroid NMDAR modulators may become a new class of compounds in the pharmacological toolbox for treating patients with NMDAR dysfunction.
Recordings of evoked excitatory postsynaptic currents in hippocampal microisland cultures reveal bidirectional modulation of synaptic NMDA receptors by endogenous neurosteroids: pregnanolone sulfate (PA-S) inhibits NMDA receptors, while pregnenolone sulfate (PE-S) has a potentiating effect.