Methamphetamine, interleukin-6 and perineuronal nets in synaptic plasticity
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Abstract
The proper functioning of the central nervous system (CNS) is dependent on the strength and integrity of neurons and their synaptic connections. Neuronal synapses allow for the flow of information that enhances cellular communication. The plasticity of these synapses essentially drives activity-dependent learning and memory. This plasticity may be enhanced and/or injured by factors including xenobiotics and components of the neural extracellular matrix (ECM). This study evaluated the effect of modulating methamphetamine (METH) action on learning and memory, the effect of METH-induced metabolites on neuronal structure and the biochemical and structural analysis of the lecticans and hyaluronan (HA) in perineuronal nets (PNNs), which are essential neural ECM components. METH is a highly addictive CNS stimulant which acts by enhancing catecholamine neurotransmission, causing euphoric, addictive, withdrawal, and neurotoxic effects. METH is clinically used in the treatment of attention-deficit/hyperactivity disorder (ADHD), narcolepsy and treatment-resistant obesity. This is however limited by the neurotoxicity effect of METH which results from oxidative stress and lipid peroxidation mechanisms. Interleukin-6 (IL6) is a pleiotropic cytokine that is a mediator of immune and inflammatory processes. IL6 is known to mediate METH-induced neurotoxicity. We used mice models to test a combination of a clinical dose of METH and IL6 deficiency on learning and memory. We showed METH-improved short-term memory with IL6 deficiency, suggesting a beneficial therapeutic effect of this combination. Next, we employed untargeted metabolomics using high-resolution liquid chromatography-mass spectrometry (LCMS) to identify differentially expressed METH metabolites. Metabolites associated with the neuronal cell membrane were identified for continued METH use, whereas a metabolite involved in cellular energetics was identified in METH withdrawal. These metabolites may hold potential therapeutic and diagnostic purposes. Finally, we solved the crystal structures of the G1 domains of two lecticans brevican and versican and used biochemical methods to characterize the valency of complexes and the kinetics of the binding affinities of lecticans and HA. The crystal structure, multimerization and relative binding affinities of the lecticans for HA suggest a basis for PNN formation. Taken together, we have shown how the synaptic plasticity may be modified and identified compounds with diagnostic and therapeutic potential.
Table of Contents
General introduction -- The effect of METH and IL6KO on learning and memory behavior in mice -- Metabolomic analysis and biomarker identification of METH use -- Analysis of the interactions between hyaluronan and lecticans in perineuronal nets -- General conclusion
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Ph.D. (Doctor of Philosophy)