Dynamic GABA and Glutamate Neurotransmission in Alzheimer's Disease and Aging

PROJECT SUMMARY / ABSTRACT It is our central hypothesis that changes in the functional properties of glutamate and GABA signaling in the hippocampus and frontal cortex in the CNS, or the glutamate/GABA balance, contribute to Alzheimer’s disease (AD) and age-related declines in cognition and memory. As outlined in NIH Notice NOT-AG-18-051 (related announcement PAR-19-070), issues surrounding age and its factor in dementia are critical in furthering our understanding of the metabolic and pathological changes that occur affecting signaling in neuronal circuits and networks. The identification of targets for existing FDA approved drugs as well as new targets for drugs to treat AD are needed and critical for treating the growing population with dementia. A major goal of this work is to determine changes to glutamate/ GABA regulatory balance in the hippocampus and frontal cortex using our MEA recording technology to study tonic (resting) and phasic (spontaneous bursts) glutamate and GABA in freely moving mice. Prior data supporting aberrant changes to glutamate and GABA systems in aging in individual brain structures, such as the rat and mouse hippocampus, are equivocal: some reports suggest increases in glutamate release while others support no change or decreases, and/or decreases, no change or increases in inhibitory GABA activity as well [9-15]. Our recent studies using a newer technology to record second-by-second tonic and phasic glutamate signaling with enzyme-based microelectrode arrays (MEAs) are designed to precisely measure discrete brain structures support that changes to glutamate release and glial uptake systems in aging are regionally heterogeneous in the striatum and hippocampus [54-56, 79]. We have also successfully adapted the MEAs for use in AD mouse models [112]. These newer methodologies used in awake animals may help to determine the mysteries surrounding glutamate/GAB interplay in an AD model and in normal aging. We plan to thoroughly investigate the glutamate and GABA systems in the hippocampus and frontal cortex in a mouse model of AD (APP/PS1 KI mice) and during normal aging. We will use behavioral tests to correlate age-related and AD model changes in glutamate and GABA using the Barnes maze (hippocampal measures), and a spatial working memory variant of the Morris water maze testing (frontal measures) to determine the behavioral capabilities of the animals. We think that because there is a dearth of treatment options our study will help in future development of therapeutics for AD. Taken together, these studies should contribute to a better understanding of the dynamics of glutamate and GABA regulation in AD and aging of the CNS.