Graduate Thesis Or Dissertation

Cannabidiol Effects on NMDA and AMPA Receptor Activity and Cognitive Function at a High Dose in 5xFAD Mice

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  • Alzheimer’s Disease (AD) is an abnormal part of aging that mainly affects those over the age of 65. The current therapies are only FDA approved for mild to moderate AD symptoms. Cannabidiol (CBD) is a non-intoxicating constituent of Cannabis sativa that has been shown to have beneficial effects on cancer, seizure treatment and pain management. CBD also shows potential as a treatment for Alzheimer’s disease, as it has been shown to decrease amyloid beta (Aβ), inflammation, and N-methyl-D-aspartate receptor (NMDA receptor) synaptic activity. The 5xFAD mouse model of amyloid overexpression showed early synaptic dysregulation of NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA receptors), via electrophysiology. By 4 months of age in the 5xFAD mice, NMDA and AMPA receptors showed increased synaptic activity compared to WT mice. The current study aimed to explore whether 2 months of CBD treatment, beginning at 2 months of age, could reduce NMDA and AMPA receptor activity back to wild type levels and improve cognitive function in the 5xFAD mice. Mice, at 4 months of age, underwent Morris water maze testing to examine long-term and associative (control) memory and cognitive flexibility. Brain tissues from mice were then examined via extracellular electrophysiology and Western blotting for glutamate receptor synaptic activity and protein expression, respectively, and immunohistochemical staining of Aβ. Male mice, regardless of genotype, treated with CBD had improved cognitive flexibility scores, but poorer long-term memory performance than males not fed CBD. WT female mice fed CBD had improved cognitive flexibility scores and increased responses for AMPA receptors, NMDA receptors and GluN2A subunits compared to WT female mice on the control diet. Electrophysiology data from heterozygous 5xFAD females was insufficiently powered to analyze. Heterozygous male mice also had increased responses for NMDA receptors and GluN2A and GluN2B subunits, but not AMPA receptors, compared to heterozygous male mice on the control diet. These results suggest, although CBD has the ability to improve cognitive flexibility, in the 5xFAD mice it does not ameliorate the increases in glutamatergic receptor activity nor improve long term memory in the presence of amyloid overexpression. CBD also does not alter the protein expression of NMDA receptor subunit or effect the Aβ plaques deposition in the 5xFAD mice.
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