RAGE SIGNALING MEDIATES DEFICITS IN HIPPOCAMPAL FUNCTION IN MODELS OF DIABETES
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Diabetes is a prevalent metabolic disorder that affects various body functions and systems. Effects of diabetes on cognitive function have been reported in animal models of diabetes, particularly learning and memory impairments and changes in hippocampal synaptic plasticity such as long-term potentiation (LTP), which depends primarily on NMDA and AMPA subtypes of glutamate receptors. The Receptor for Advanced Glycation End-products (RAGE) has been particularly implicated in vascular and peripheral nervous system complications of diabetes. These observations led us to hypothesize that RAGE signaling in models of diabetes can alter the function of NMDA and AMPA subtypes of glutamate receptors, leading to dysfunction in synaptic transmission and subsequent impairment in learning and memory. Our findings showed that although recognition memory was unaffected in streptozotocin (STZ)-induced diabetes in both genotypes, hippocampal-dependent spatial memory was impaired in STZ-induced diabetic mice in wild-type (WT) but not in the RAGE knockout (RAGE-KO) group. This impairment in spatial memory was consistent with deficits in synaptic plasticity, i.e. LTP and paired pulse facilitation (PPF), and reduction in the expression and phosphorylation of the GluA1 subunit of the AMPA receptor in WT STZ-induced diabetic mice. These changes were associated with the activation of the mitogen activated protein kinase (MAPK) pathway, leading to increased total p38, phospho-p38, and nuclear factor-kappa beta (NF-κB) and decreased phospho c-Jun N-terminal kinase (pJNK) and its kinase, mitogen activated protein kinase kinase 7 (pMEK7). In WT hippocampal cultures, high glucose caused a reduction of AMPA-evoked currents, as well as a reduction in cell excitability, and an increase in cytosolic ROS. This is the first study, to the best of our knowledge, that shows the contribution of RAGE signaling in abnormal hippocampal synaptic transmission and cognitive function in diabetes, which could help identify potential targets for therapeutic interventions.
DegreeDoctor of Philosophy (Ph.D.)
SupervisorCampanucci , Veronica
CommitteeFisher, Thomas; Mousseau , Darrel; Bekar, Lane K; Howland, John
Copyright DateSeptember 2019
Diabetes, RAGE, hippocampus, synaptic plasticity, cognitive function