BDNF and Astrocyte TrkB.T1 Signaling as a Mechanism Underlying Astrocyte Synapse Interactions in Motor and Barrel Cortex

Synapses are the fundamental units of communication in the brain, and their proper development and function are critical for cognitive processes and behavior. While the development of glutamatergic synapses has been extensively studied, the mechanisms underlying the formation of the tripartite synapse remain poorly understood. The tripartite synapse is a specialized structure consisting of the presynaptic terminal, the postsynaptic element, and a perisynaptic astrocyte process (PAP) that ensheathes the synaptic cleft. Increasing evidence demonstrates that PAPs are critical for synapse formation, stabilization, and plasticity. However, the mechanisms that govern the formation of tripartite synapses remain to be fully elucidated. This dissertation investigates the role of the astrocyte TrkB.T1 receptor, a truncated isoform of the canonical receptor for brain derived neurotrophic factor (BDNF), in mediating behavior and excitatory synapse development. Using an astrocyte-specific conditional TrkB.T1 knockout mouse model, we demonstrate that deletion of TrkB.T1 results in hyperactive locomotion, with increased voluntary running and perseverative motor behaviors. Through a combination of molecular and cellular approaches, we demonstrate that the behavioral abnormalities that result from TrkB.T1 deletion are accompanied by developmental reductions in glutamatergic synapses and astrocyte-synapse interactions in the motor and barrel cortex. Mechanistic studies using neuron-astrocyte co-cultures also reveal that loss of TrkB.T1 in astrocytes inhibits the formation of PAPs around glutamatergic synapses. Altogether, the insights presented herein present a novel astrocyte-mediated signaling mechanism that regulates excitatory synapse formation. These insights have important implications for understanding both neurodevelopmental and neuropsychiatric disorders involving synaptic dysfunction.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Neuroscience

Department dc:contributor.department

Neuroscience

Grantor dc:publisher

Virginia Tech

Year dc:date.issued

2024

Author dc:creator

• Pinkston, Beatriz T. Ceja

Chair dc:contributor.committeechair

• Olsen, Michelle Lynne

Committee members dc:contributor.committeemember

• Fox, Michael A.
• Robel, Stefanie
• English, Daniel F.
• Swanger, Sharon Ann

• Astrocytes
• synapse development
• BDNF
• TrkB
• astrocyte-synapse interactions
• perisynaptic astrocyte processes

Statement dc:rights

• Creative Commons Attribution-NoDerivatives 4.0 International

Licence dc:rights.uri

• http://creativecommons.org/licenses/by-nd/4.0/

Language dc:language.iso

en

Dc Identifier Other

vt_gsexam:41131

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/120699