Current psychiatric pharmacotherapy options leave much to be desired, and manipulation of N-methyl-D-aspartate receptors (NMDARs) by positive and negative regulators has therapeutic benefit in major psychiatric disorders including schizophrenia and depression. We propose to capitalize on our recent discovery of a novel, very potent, and potentially endogenous positive modulator of NMDARs. The prototype is the major cholesterol metabolite in brain, 24S-hydroxycholesterol (24OH). Oxysterols like 24OH are cellular lipids generated from oxidation of cholesterol. Prevailing views suggest 24OH is synthesized as a convenient waste disposal vehicle for the neuronal pool of cholesterol that turns over in brain, but we have discovered that 24OH modulates NMDAR function at concentrations well below those measured in brain. We will leverage innovative chemical biology and physiological approaches toward understanding the mechanisms of 24OH. Our preliminary data suggest that 24OH and a synthetic analogue, Org-1, have unusual potentiating actions at NMDARs that are antagonized by another cholesterol metabolite, 25-hydroxycholesterol. We hypothesize that 24OH has direct effects on NMDAR channel gating through a novel receptor binding site. To understand mechanisms of oxysterol neuromodulation, we exploit a longstanding interdisciplinary collaboration with a synthetic chemistry laboratory, directed by Douglas Covey. We propose to use novel chemical tagging strategies to create analogues for cell biological and physiological studies. These approaches will yield insight into subcellular domains of exogenous oxysterol actions and insight into the peculiar kinetics of oxysterol action. We will also investigate the effects of 24OH and Org-1 on synaptic plasticity and behavior in wild type mice and in mice deficient in the enzyme that produces 24OH. Preliminary data suggest that 24OH and Org-1 enhance synaptic plasticity and cognition. This work will be complemented by measurements of endogenous 24OH and Org-1 levels under varied experimental conditions by collaborators at Weill Cornell Medical College. We have a strong interdisciplinary track record that will foster rapid progress. Upon completion of these studies, we expect to have elucidated mechanisms and effects of a novel neuromodulator with broad importance.
Current psychiatric pharmacotherapy options leave much to be desired, and NMDA receptor modulators show promise. Here we characterize the pharmacological properties and behavioral effects of novel endogenous NMDA receptor modulators. The main cholesterol metabolite in brain has potent positive modulatory actions, and another class of cholesterol metabolite inhibits the modulation. Thus, we explore a new push-pull system of interaction with a receptor class important to brain plasticity and disease.
|Chakrabarti, Sampurna; Qian, Mingxing; Krishnan, Kathiresan et al. (2016) Comparison of Steroid Modulation of Spontaneous Inhibitory Postsynaptic Currents in Cultured Hippocampal Neurons and Steady-State Single-Channel Currents from Heterologously Expressed Î±1Î²2Î³2L GABA(A) Receptors. Mol Pharmacol 89:399-406|
|Sun, Min-Yu; Izumi, Yukitoshi; Benz, Ann et al. (2016) Endogenous 24S-hydroxycholesterol modulates NMDAR-mediated function in hippocampal slices. J Neurophysiol 115:1263-72|
|Ishikawa, Makoto; Yoshitomi, Takeshi; Zorumski, Charles F et al. (2016) 24(S)-Hydroxycholesterol protects the ex vivo rat retina from injury by elevated hydrostatic pressure. Sci Rep 6:33886|
|Emnett, Christine; Li, Hairong; Jiang, Xiaoping et al. (2016) A Clickable Analogue of Ketamine Retains NMDA Receptor Activity, Psychoactivity, and Accumulates in Neurons. Sci Rep 6:38808|
|Zorumski, Charles F; Izumi, Yukitoshi; Mennerick, Steven (2016) Ketamine: NMDA Receptors and Beyond. J Neurosci 36:11158-11164|
|Sun, Min-Yu; Linsenbardt, Andrew J; Emnett, Christine M et al. (2016) 24(S)-Hydroxycholesterol as a Modulator of Neuronal Signaling and Survival. Neuroscientist 22:132-44|
|Jiang, Xiaoping; Shu, Hong-Jin; Krishnan, Kathiresan et al. (2016) A clickable neurosteroid photolabel reveals selective Golgi compartmentalization with preferential impact on proximal inhibition. Neuropharmacology 108:193-206|
|Izumi, Yukitoshi; O'Dell, Kazuko A; Zorumski, Charles F (2015) Corticosterone enhances the potency of ethanol against hippocampal long-term potentiation via local neurosteroid synthesis. Front Cell Neurosci 9:254|
|Izumi, Yukitoshi; Zorumski, Charles F (2015) Sensitivity of N-methyl-D-aspartate receptor-mediated excitatory postsynaptic potentials and synaptic plasticity to TCN 201 and TCN 213 in rat hippocampal slices. J Pharmacol Exp Ther 352:267-73|
|Stein, Liana Roberts; Zorumski, Charles F; Imai, Shin-Ichiro et al. (2015) Nampt is required for long-term depression and the function of GluN2B subunit-containing NMDA receptors. Brain Res Bull 119:41-51|
Showing the most recent 10 out of 17 publications