Wednesday, April 2, 2025
4/2/2025
Dynamic GABA and Glutamate Neurotransmission in Alzheimer’s Disease and Aging - PROJECT SUMMARY / ABSTRACT Alzheimer’s disease (AD) progression and normal aging are complex and often heterogeneous processes involving functional changes to neuronal and glial elements that are not just related to neuronal cell loss [1-4, 143]. Prior in vitro and in vivo data support that aberrant regulation of glutamate neuronal systems can be a contributor to neuronal degeneration in aging and likely a contributor to the age-dependent development of AD [1, 4, 6-8]. We think that because there is a dearth of treatment and monitoring options our study will help in the future development of therapeutics and non-invasive spectroscopic monitoring techniques for AD. Recently, we have successfully adapted our enzyme-based microelectrode arrays (MEAs), which are designed to precisely measure tonic and phasic neurotransmitter release in discrete brain structures in awake animals, for use in aged rodents and AD mouse models [54-56, 79, 112]. A major knowledge gap in AD and aging involves changes in the excitatory/inhibitory balance between glutamate (Glu) and GABA release and regulation [9-15]. We believe that the use of our new recording technology will improve our understanding of the glutamate/GABA interplay in an AD model and in normal aging. Our recent studies using this superior technology now allows the measurements of tonic and phasic glutamate levels found that rats >18 months of age have normal or elevated basal Glu levels compared to younger rats. Thus, some animals have elevated glutamate while others do not. As outlined in NIH Notice NOT-AG-18-051 & related announcement PAR-19-070, issues surrounding age and its role in dementia are critical in furthering our understanding of the metabolic and pathological changes that affect signaling in neuronal circuits and networks. We will use young and aged normal and the APPNLh/NLh x PS1P264L/P264L knock-in mouse (APP/PS1 KI) that does not overexpress APP or PS1, or use artificial promoters, making it an ideal system for the study of how aging affects the development of AD-related neuropathology [86- 90]. We will use our novel methods to simultaneously record GABA and glutamate signaling in either the CA1 region of the hippocampus or Frontal Cortex. We will first behaviorally characterize all animals so that we can determine potential correlations between the behavioral performance of mice and glutamate and GABA release and/or regulation in the hippocampus (Morris water maze test) and frontal cortex (spatial memory variant of Morris water maze test) [115] and performed as per [116]. Finally, mice that are studied will undergo a pathological examination to evaluate neurodegeneration by evaluating reactive gliosis may be present by looking at Iba1 and GFAP. Collectively, these studies will allow us to compare the effects of normal aging in male and female to the effects seen from a mouse model of AD on the balance of glutamate and GABA signaling and its relationship(s) to cognitive function in both male and female animals towards the development of novel therapeutics to possibly treat the development and progression of AD.
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