Jack-of-all-trades, The Role of Astrocytes in Circuit Formation and Plasticity
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Date
2020-06
Authors
Perez-Catalan, Nelson A.
Journal Title
Journal ISSN
Volume Title
Publisher
University of Oregon
Abstract
Neurons are electrically excitable cells that transmit information throughout the
nervous system with high speed and accuracy. This is largely facilitated by their
specialized morphology, with dendrites receiving diverse information, to axons
propagating the message to specific neighboring neuronal partners. During
development, neuronal networks undergo rapid changes, ranging from short-term
changes on the order of milliseconds, to long-term modifications in neural architecture
that could last as long as the lifetime of the organism. This ‘plasticity’ ensures that
neuronal networks, or circuits, undergo constant checks during development, while also
facilitating a degree of adaptability that acts as the basis for learning and memory. The
mechanisms that the nervous system employs to establish the correct connections and
regulate plasticity remain a poorly understood topic in neuroscience. Research in both
mammals and invertebrates, including Drosophila, have defined that glial cells are
capable of instructing neurons to find partners to form synapses, a specialized chemical
junction between two neurons where electrical signals propagate. More specifically,
studies in astrocytes, the most abundant glial cell subtype in the central nervous system,
have demonstrated that while neurogenesis precedes astrogenesis in the cortex, neuronal
synapses only begin to form after astrocytes have been generated (explored in Chapter
1). Astrocyte development is crucial for circuit formation in the nervous system, and
their dysfunction can lead to neurodevelopmental, neurodegenerative, neuroimmune,
and neoplastic diseases, such as ALS and Alzheimer’s. This thesis explores a subset of
the mechanisms employed by the nervous system to regulate circuit plasticity and
circuit establishment during development, with a specific focus on astroglia.
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My first goal was to characterize plasticity within a model neural circuit during
development. In the second chapter of this thesis, I use the highly specialized genetic
toolkit available for Drosophila to characterize the structural dynamics of motor neuron
dendrites during development in vivo by utilizing fluorescence microscopy. By
manipulating neuronal activity in my model motor neurons, I show that the presence of
stable microtubule populations within dendrites is directly correlated with structurally
stable arbors. Furthermore, overexpression of the cell adhesion molecule Neurexin in
motor neurons led to the increased stability of microtubule populations within dendritic
arbors. Finally, I demonstrate that astrocytes are required to restrict motor dendrite
plasticity to newly hatched larva. Interestingly, astrocytes robustly express Neuroligins,
which are binding partners for Neurexin, suggesting that astrocyte-secreted proteins are
capable of directly regulating neuronal morphology and plasticity.
Previous studies in vitro have shown that in addition to regulating circuit
plasticity, astrocyte-derived secreted and cell surface molecules (CSMs) can modify
synaptogenesis during circuit development. In a separate line of questioning, I explore
the role of astrocyte-secreted and cell surface proteins in the formation of excitatory
cholinergic synapses in vivo (described in Chapter 3). Specifically, I took part in a
reverse genetic screen to knock down astrocyte-derived proteins using commercially
available RNAi lines. Concurrently, we labeled both neuronal membranes and their presynaptic
sites (Brp+) using Synaptic Tagging with Recombination (STaR) to assess
non-cell autonomous changes in synapse number. We performed two parallel screens,
the first labeled individual dorsal bipolar dendritic (Dbd) sensory neurons. The second
targeted neurons that generate synapses localized in the mushroom body, a memory and
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learning center in the Drosophila brain. Excitingly, the major astrocyte-secreted
molecules that induce synapse formation (e.g. TGF-β) or inhibit synapse development
(e.g. SPARC) in vertebrates are conserved in fly, and we identified fourteen novel genes
(of 245 tested) required in astrocytes for synaptogenesis.
In sum, this work further characterizes dendritic dynamics during a critical
period in Drosophila development. My data shows that altered neuronal activity in
aCC/RP2 motor neurons within a critical period of motor circuit plasticity causes
significant dendritic remodeling within minutes, and that astrocytes are required for
proper critical period closure. Further, I demonstrate that the ablation of astrocytes postcritical
period induces abnormal period of heightened plasticity. Finally, this work
provides direct evidence of the key regulatory function of astrocytes in synaptogenesis,
and their role in regulating global synapse formation in the central nervous system.
Description
Submitted to the Undergraduate Library Research Award scholarship competition: 2020. 94 pages.