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. / Doctor of Philosophy / Synapses are the central unit of communication in the brain. These neurochemical hubs of communication are able to orchestrate systems and overall behavior. Classically, a synapse has been defined as the contact point of communication between a pre-synaptic terminal and an apposing post-synaptic element. Simply illustrated, pre-synaptic terminals release neurotransmitters that can bind to the receptors of post-synaptic elements, enabling for either excitatory or inhibitory communication. While the field of neuroscience has studied how synapses form and mature, there are still many unanswered questions about a specialized synaptic structure called the tripartite synapse.
The tripartite synapse involves not just a pre- and post-synaptic element, but also a third player – a multitasking cell called the astrocyte. Astrocytes extend thousands of fine, leaflet-like processes that wrap around and support neuronal synapses. These processes, termed perisynaptic astrocyte processes (PAPs), are critical for synaptic development and function.
This dissertation investigated how brain derived neurotrophic factor (BDNF) and its receptor TrkB.T1, found almost exclusively in astrocytes, control the formation of PAPs during brain development. Using a combination of advanced microscopy and cellular and molecular techniques, we demonstrate that BDNF/TrkB.T1 signaling in astrocytes acts as a critical regulator in the development of synapses and astrocyte-synapse interactions, instructing astrocytes to extend processes that can ensheath synapses as they mature. Disruption of this pathway in mice also led to hyperactive behavior, underscoring its importance for proper brain development and function.
This novel astrocyte-based mechanism governing synapse maturation has important implications for understanding neurodevelopmental and neuropsychiatric disorders and could ultimately lead to novel therapeutic strategies targeting synaptic defects in these conditions.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/120699 |
| Date | 25 July 2024 |
| Creators | Pinkston, Beatriz T. Ceja |
| Contributors | Neuroscience, Olsen, Michelle Lynne, Fox, Michael A., Robel, Stefanie, English, Daniel F., Swanger, Sharon Ann |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Language | English |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf |
| Rights | Creative Commons Attribution-NoDerivatives 4.0 International, http://creativecommons.org/licenses/by-nd/4.0/ |
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