Preferential enhancement of GluN2B-containing native NMDA receptors by the endogenous modulator 24S-hydroxycholesterol in hippocampal neurons

Abstract 24S-hydroxycholesterol (24HC) is the major metabolic breakdown product of cholesterol in the brain. Among its other effects on neurons, 24HC modulates N-methyl- d -aspartate (NMDA or GluN) receptors, but our understanding of this mechanism is poor. We used whole-cell patch clamp recordings and various pharmacological approaches in mouse brain slices to record isolated NMDAR-mediated (I NMDA ) tonic and evoked synaptic currents. 24HC (1 μΜ) significantly enhanced tonic, but not evoked, I NMDA of dentate gyrus granule cells. The I NMDA had both GluN2A and GluN2B-mediated components. Preincubation of the slices with PEAQX (a GluN2A antagonist) or Ro25-6981 (a GluN2B antagonist) dramatically changed the I NMDA modulatory potential of 24HC. Ro25-6981 blocked the enhancing effect of 24HC on tonic I NMDA , while preincubation with PEAQX had no effect. In cholesterol 24-hydroxylase (CYP46A1) knockout mice, in sharp contrast to WT, 24HC slightly decreased the tonic I NMDA of granule cells. Furthermore, 24HC had no effect on tonic I NMDA of dentate gyrus parvalbumin interneurons (PV-INs), known to express different GluN subunits than granule cells. Taken together, our results revealed a specific enhancement of GluN2B-containing NMDARs by 24HC, indicating a novel endogenous pathway to influence a subclass of NMDARs critically involved in cortical plasticity and in numerous neurological and psychiatric disorders.