The major brain cholesterol metabolite 24(S)-hydroxycholesterol is a potent allosteric modulator of N-methyl-D-aspartate receptors.

TitleThe major brain cholesterol metabolite 24(S)-hydroxycholesterol is a potent allosteric modulator of N-methyl-D-aspartate receptors.
Publication TypeJournal Article
Year of Publication2013
AuthorsPaul SM, Doherty JJ, Robichaud AJ, Belfort GM, Chow BY, Hammond RS, Crawford DC, Linsenbardt AJ, Shu H-J, Izumi Y, Mennerick SJ, Zorumski CF
JournalJ Neurosci
Volume33
Issue44
Pagination17290-300
Date Published2013 Oct 30
ISSN1529-2401
KeywordsAction Potentials, Allosteric Regulation, Animals, Cholesterol, Female, Hippocampus, Hydroxycholesterols, Male, Mice, Organ Culture Techniques, Rats, Rats, Long-Evans, Rats, Sprague-Dawley, Receptors, N-Methyl-D-Aspartate
Abstract

N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels that are critical to the regulation of excitatory synaptic function in the CNS. NMDARs govern experience-dependent synaptic plasticity and have been implicated in the pathophysiology of various neuropsychiatric disorders including the cognitive deficits of schizophrenia and certain forms of autism. Certain neurosteroids modulate NMDARs experimentally but their low potency, poor selectivity, and very low brain concentrations make them poor candidates as endogenous ligands or therapeutic agents. Here we show that the major brain-derived cholesterol metabolite 24(S)-hydroxycholesterol (24(S)-HC) is a very potent, direct, and selective positive allosteric modulator of NMDARs with a mechanism that does not overlap that of other allosteric modulators. At submicromolar concentrations 24(S)-HC potentiates NMDAR-mediated EPSCs in rat hippocampal neurons but fails to affect AMPAR or GABAA receptors (GABA(A)Rs)-mediated responses. Cholesterol itself and other naturally occurring oxysterols present in brain do not modulate NMDARs at concentrations ≤10 μM. In hippocampal slices, 24(S)-HC enhances the ability of subthreshold stimuli to induce long-term potentiation (LTP). 24(S)-HC also reverses hippocampal LTP deficits induced by the NMDAR channel blocker ketamine. Finally, we show that synthetic drug-like derivatives of 24(S)-HC, which potently enhance NMDAR-mediated EPSCs and LTP, restore behavioral and cognitive deficits in rodents treated with NMDAR channel blockers. Thus, 24(S)-HC may function as an endogenous modulator of NMDARs acting at a novel oxysterol modulatory site that also represents a target for therapeutic drug development.

DOI10.1523/JNEUROSCI.2619-13.2013
Alternate JournalJ. Neurosci.
PubMed ID24174662
PubMed Central IDPMC3812502
Grant ListAA017413 / AA / NIAAA NIH HHS / United States
GM47969 / GM / NIGMS NIH HHS / United States
MH077791 / MH / NIMH NIH HHS / United States
MH078823 / MH / NIMH NIH HHS / United States
R01 MH078823 / MH / NIMH NIH HHS / United States
T32 DA007261 / DA / NIDA NIH HHS / United States