Electronic Theses and Dissertations

Date of Award

1-1-2020

Document Type

Dissertation

Degree Name

Ph.D. in Pharmaceutical Sciences

First Advisor

Nicole Ashpole

Second Advisor

Kristine Willett

Third Advisor

Joshua Sharp

School

University of Mississippi

Relational Format

dissertation/thesis

Abstract

Levels of Insulin-like growth factor I (IGF-1) are reduced in several neurological disorders, including aging and neurodegeneration. Aged animals have reduced IGF1 signaling and exhibit impairment in cognition. Supplementing rodents with IGF-1 reverses some of the cognitive deficit, suggesting that IGF-1 signaling could potentially be targeted to ameliorate cognitive decline in older adults. For this, a thorough understanding of the mechanisms by which IGF-1 regulates the function of various cell types in the brain is needed. A majority of studies have focused on the effects of IGF-1 regulating neurons. However, astrocytes that form roughly about 40% of brain mass also produce IGF-1 and express IGFR. Studies have shown that IGF-1 regulates some of the astrocytic functions like glucose uptake. Based on these observations, we hypothesized that loss of IGF-1 signaling disrupts astrocyte structure, and its critical function of glutamate-glutamine cycling, ultimately affecting cognition. To test this, we used a combination of pharmacological and genetic manipulations to reduce IGFR in cultured astrocytes and mice. We observed that loss of IGF1 signaling in astrocytes decreases uptake of glutamate by decreased trafficking or expression of glutamate uptake transporter machinery. To test the effect of loss of astrocytic IGF-1 signaling on cognition, we generated a mouse model of inducible astrocytic IGFR deficiency by crossing homozygous igfrf/f mice with iGFAP-Cre mice using tamoxifen. We then assessed the role of astrocytic IGFR in regulating behavior using a battery of behavioral assays. Consistent with the in vitro results, we observe disrupted glutamate handling and neurotransmitter cycling in the brains of astrocyte-specific IGFR (aIGFR) KO animals. Additionally, we also observe increase in the levels of urea in the brain, which is indicative of neuronal stress. aIGFR knockout animals do not show any impairment in cognition, suggesting astrocytic IGFR does not contribute to cognitive decline due to loss of IGF-1 Thus, loss of IGF-1 signaling in astrocytes affects glutamate homeostasis which may contribute to the development of an excitotoxic phenotype observed in aging and neurodegeneration. Overall, this project helped uncover critical aspects of IGF1 regulation of astrocyte structure, function and cognition.

Available for download on Tuesday, August 31, 2021

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