Fariba, Farnosh; (2003) Modulation of the AMPA Receptor by Membrane cholesterol and neuroactive steroids. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Cholesterol in the plasma membrane of cells has been found to modulate the actions of various proteins in the membrane. This thesis describes the influence of membrane cholesterol on the excitatory AMPA receptor in acutely dissociated rat hippocampal neurones. Non-genomic influences of acute exposure to neuroactive steroids on the function of the AMPA receptor have also been investigated. Neuronal membrane cholesterol levels were altered by means of the cholestrol carrier methyl-β-cyclodextrin. Using the patch clamp technique, whole cell current responses to local applications of AMPA were recorded. Depletion of cholesterol to 62% control increased the potency of AMPA, whilst enrichment to 205% control decreased the potency of AMPA and the maximum response obtainable. The AMPA responses showed rapid desensitization, which was reduced in cholesterol-depleted neurones and increased in cholesterol-enriched neurones. NBQX antagonised responses to AMPA competitively but failed to affect the relationship between desensitization and AMPA concentration. GYKI 52466 reduced the maximum response to AMPA and shifted the desensitization profile to higher AMPA concentrations. The neuroactive steroids pregnenolone sulphate, deoxycorticosterone, corticosterone and progesterone reduced the maximum response to AMPA and reduced its potency whereas tetrahydrodeoxycorticosterone, allopregnanolone and epiallopregnanolone simply reduced the potency of AMPA. The 5β isomers of the former two steroids were inactive. Cholesterol depletion enhanced and enrichment diminished the reductions in AMPA potency by all of the active steroids. Possible mechanisms underlying these novel observations with cholesterol and the neuroactive steroids include membrane fluidity changes and specific modulatory sites for specific steroids on the AMPA receptor protein. These are further discussed.

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