The effects of synthetic glucocorticoid treatment on synaptic physiology

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)

Abstract

Glucocorticoids are one of the most commonly prescribed classes of drug due to their potent anti-inflammatory effects. However, patients often report a number of side effects including memory impairment and mood changes, but the underlying mechanisms remain unresolved. It has recently been demonstrated that chronic treatment with the synthetic glucocorticoid methylprednisolone (MPL) disrupts the circadian regulation of clock genes in the hippocampus, and that dynamic transcription profiles of synaptic gene products are dysregulated as a result. In this thesis, by utilising extracellular electrophysiological recording techniques, I show that chronic MPL treatment also results in deficits in the circadian regulation of hippocampal synaptic plasticity in the brain slice preparation. Further to this, I demonstrate that synaptic plasticity is similarly disrupted in the perirhinal cortex. The deficits in synaptic plasticity appear to be specific to stimulation protocols that rely on activation of N-methyl-D-aspartate (NMDA) receptors, specifically those containing the GluN2B subunit. Whole-cell patch clamp recordings revealed that MPL inverted the circadian rhythms in spontaneous excitatory neurotransmission in these regions. Spontaneous glutamatergic transmission was also altered in medial prefrontal cortex (mPFC) at both the circadian peak and nadir, while inhibitory currents in all regions were much less liable to steroid-induced changes. Therefore, chronic MPL exposure led to alterations to the delicate balance between excitation and inhibition. I provide further electrophysiological evidence showing that MPL treatment alters glutamate receptor ratios in pyramidal cells of the hippocampus, perirhinal cortex, and prelimbic mPFC. These data reveal a novel role for glucocorticoids in the circadian regulation of neural activity in the brain, and provide mechanistic insight to aid the understanding of mnemonic deficits associated with chronic synthetic glucocorticoid treatment.
Date of Award21 Jun 2022
Original languageEnglish
Awarding Institution
  • University of Bristol
SupervisorStafford L Lightman (Supervisor), Zuner Bortolotto (Supervisor) & Becky Conway-Campbell (Supervisor)

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