All ETDs from UAB

Advisory Committee Chair

Lori L McMahon

Advisory Committee Members

David Knight

Christianne Strang

Erik Roberson

Franklin Amthor

Qin Wang

Document Type

Dissertation

Date of Award

2020

Degree Name by School

Doctor of Philosophy (PhD) College of Arts and Sciences

Abstract

The central noradrenergic (NA) system is critical for maintenance of attention, behavioral flexibility, spatial navigation, and learning and memory, those cognitive functions lost first in early Alzheimer’s disease (AD). In fact, the locus coeruleus (LC), the major source of norepinephrine (NE) in brain, is the first site of pathological tau accumulation in human AD associated with axon loss throughout forebrain, including hippocampus. The dentate gyrus (DG) is heavily innervated by LC-NA axons, where released norepinephrine (NE) acts on β adrenergic receptors (ARs) at excitatory synapses from entorhinal cortex (EC) to facilitate long-term synaptic plasticity and memory formation. These synapses show dys-function in early AD prior to cognitive impairment. In the TgF-344-AD rat model, degen-eration of LC-NA axons in hippocampus recapitulates human AD, providing a preclinical model to investigate synaptic and behavioral consequences. Using biochemistry and brain slice electrophysiology in 9 month old male wild type and TgF344-AD rats, we discovered that loss of LC-NA axons coincides with heightened β-AR function at medial perforant path-dentate granule cell synapses (MPP-DCG). Heightened β-AR function is responsible for the increase in LTP magnitude at MPP-DCG synapses previously reported in TgF344-AD rats. This possible compensatory heightened β-AR function could preserve learning and memory. Indeed, novel object recognition is facilitated in TgF344-AD rats, and phar-macological blockade of β-ARs unmasks a deficit in extinction learning in TgF344-AD rats indicating a greater reliance on β-ARs in these behavioral tasks. Thus, a compensatory increase in β-AR function during prodromal AD heightens synaptic plasticity that contrib-utes to a preservation of learning and memory.

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