All ETDs from UAB

Advisory Committee Chair

Gwendalyn D King

Advisory Committee Members

Jeremy H Herskowitz

Farah D Lubin

Lucas Pozzo-Miller

Scott M Wilson

Document Type

Dissertation

Date of Award

2019

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Klotho protein expression has profound effects on lifespan where klotho-deficient mice exhibit premature aging phenotypes and live only to ~8 weeks of age while klotho-overexpressing mice have lifespans that are at least 20% longer than wild-type mice. Klotho expression also has similar effects on cognitive function as klotho-deficient mice develop cognitive impairment by 7 weeks of age and klotho-overexpressing mice show enhanced cognitive function. These effects also extend to humans as polymorphisms that alter circulating levels of klotho have likewise effects on lifespan and brain function. Despite the fact that modulation of klotho expression has reciprocal effects on cognitive function, the role that klotho plays in the brain has not been extensively characterized. This work endeavored to understand how klotho affects neuronal function since klotho is expressed in neurons throughout the brain parenchyma. This work determines the subcellular localization of klotho within neurons and establishes its expression at the synapse. Consistent with the expression of klotho at the synapse and its impact on cognitive function, we show that klotho regulates synaptic plasticity of Schaffer collateral synapses in the hippocampus, but we also discovered that altering klotho expression leads to dissociations between synaptic plasticity and memory. As memory, synaptic plasticity, and synaptic structure are closely linked, we measured the effects of klotho on dendritic spine morphology and found that more spines from klotho-deficient neurons favored mature morphology while more klotho-overexpressing spines favored immature morphology. With these structural results suggesting a possible reason for altered synaptic physiology, we turned our focus to the reduced system of primary neuronal cultures to characterize the effects of klotho-deficiency specifically on neurons. We found that klotho-deficiency increased neuronal network synchrony such that chronically stimulating neuronal activity resulted in significantly elevated and sustained synchronous network activity compared to wild-type neurons. Consistent with this, we found that, in vivo, klotho-deficient mice were more susceptible to seizure induction. Together, these data demonstrate a direct effect of klotho on neurons, specifically affecting synaptic function. Thus, the effect of klotho on cognitive function may be influenced by its effects on neuronal morphology resulting in changes to network-wide activity.

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