All ETDs from UAB

Advisory Committee Chair

Michelle L Olsen

Advisory Committee Members

Rita Cowell

John J Hablitz

Lucas Pozzo-Miller

Lori L McMahon

Document Type

Dissertation

Date of Award

2019

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Astrocytic morphogenesis and maturation are critical steps in central nervous system (CNS) development. During morphological maturation, astrocytes extend fine peripheral processes which infiltrate the neuropil and form intimate partners with neuronal structures, including synapses, where they facilitate neurotransmitter and K+ uptake and contribute to synaptic development and stabilization. The developmental time window of astrocyte morphological maturation and refinement is well defined, but the molecular mechanisms that underlie this process are not understood. Brain derived neurotrophic factor (BDNF) is a critical growth factor involved in the development and maturation of neurons. We developed a novel technique for the specific isolation of cell populations from rodents from early postnatal development through adulthood. Utilization of this technique to examine neurons, astrocytes, and microglia demonstrated that Ntrk2, the gene that encodes BDNF’s receptor, is enriched in astrocytes relative to all CNS cell populations, including neurons. RNA Sequencing and quantitative PCR data demonstrate astrocytic Ntrk2 expression is almost exclusively due to the truncated TrkB receptor, TrkB.T1. We demonstrate that astrocytes functionally respond to BDNF with significant increases in morphological complexity in vitro, which is dependent upon the presence of astrocytic TrkB.T1. Furthermore, genetic deletion of TrkB.T1 in vivo reveals astrocytes with significantly reduced volume and branching complexity. Indicating a role for functional astrocyte maturation via BDNF/TrkB.T1 signaling, TrkB.T1 KO astrocytes exhibit decreased mature astrocytic markers, aberrant synaptogenic factor expression, and do not support normal excitatory synaptogenesis. Together, these data suggest a significant role for BDNF/TrkB.T1 signaling in astrocyte morphogenesis and indicate this signaling may contribute to astrocyte regulation of neuronal synapse development.

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