NMDARs
NMDARs are glutamate-gated ion-channels critical in the regulation of excitatory synaptic function. They are involved in experience-dependent synaptic plasticity and implicated in the cognitive defects of schizophrenia and some forms of autism (Paul et al., 2013). 24S-HC is a positive allosteric modulator (PAM) of NMDARs interacting with the receptors at a site distinct from other allosteric modulators e.g. the PAM pregnenolone sulphate. Even at sub-micromolar concentrations 24S-HC potentiates NMDAR-mediated excitatory post synaptic currents (EPSC) and enhances long term potentiation (LTP) (Paul et al., 2013). While the presence of pregnenolone sulphate in brain is debatable (Liu, Sjovall & Griffiths, 2003), 24S-HC is present in rodent and human brain at concentrations of 10 – 20 ng/mg (25 – 50 µM). Importantly, 24S-HC does not alter membrane currents on its own, indicating that the effect is independent of nuclear receptors e.g. LXR. The synthetic 24-HC analogue, 24,24-dimethylchol-5-en-3β,24-diol (SGE-201), is also a PAM, somewhat more potent than the parent molecule, and it likewise potentiates LTP and, remarkably, reverses behavioural deficits (e.g. spatial working memory) induced by NMDAR channel blockers (Paul et al., 2013). Importantly, the Cyp46a1-/- mouse shows a deficiency in hippocampal LTP and a deficit in spatial, associative, and motor learning (Kotti, Ramirez, Pfeiffer, Huber & Russell, 2006). This was explained by Kotti et al to be a consequence of reduced flux of metabolites through the cholesterol biosynthetic pathway and the through the mevalonate pathway towards geranylgeraniol diphosphate (Kotti, Ramirez, Pfeiffer, Huber & Russell, 2006). Administration of geranylgeraniol to hippocampal slices restored LTP to wild type levels indicating that it is a deficit in this molecule, or its diphosphate, which is responsible for the impaired LTP in theCyp46a1-/- mouse (Kotti, Head, McKenna & Russell, 2008; Kotti, Ramirez, Pfeiffer, Huber & Russell, 2006). In light of the data of Paul et al indicating that 24S-HC is a PAM (Paul et al., 2013), it is not unreasonable to speculate that a loss of this molecule in the Cyp46a1-/- mouse may also be responsible for some of the deficiency in hippocampal LTP. It is likely that 24S-HC modulates NMDARs in an autocrine or paracrine manner at a distinct site from other PAMs (Paul et al., 2013). Surprisingly, the other side-chain oxysterols 22R-HC and 20S-HC are not modulators of NMDARs, although 25-HC is a weak positive modulator (Linsenbardt et al., 2014; Paul et al., 2013). In-fact, 25-HC is an antagonist of the PAM activity of 24S-HC to NMDARs, but remarkably through a different site (Linsenbardt et al., 2014).