Transcriptional Correlates of Homeostatic Plasticity and Neuronal Diversity at the Neuromuscular Junction
Synapses are specialized intercellular junctions between a neuron and its target that allows for rapid communication between cells. Neurons and their synapses have multiple adaptive mechanisms to stabilize communication in response to a barrage of different environmental challenges. While there is an enormous body of literature on the mechanisms of these phenomena from a functional standpoint, less is known about (1) how these processes are orchestrated at the genetic level and (2) how differences in neuron type inform the capacity to enact such mechanisms.
To address these questions I turn to the Drosophila larval neuromuscular junction (NMJ). The Drosophila NMJ is a model glutamatergic synapse in which a motor neuron communicates with the body wall muscles to control motor output. Each muscle fiber receives input from two different types of glutamatergic neurons, each of which has unique physiological properties. Previous work has shown that blocking the receipt of glutamate by the downstream muscle by genetic mutation results in a retrograde homeostatic mechanism that potentiates synaptic transmission in a manner specific to neuronal subtype. The molecular and genetic determinants of this process are a mystery in the field, opening up even more questions about how gene expression can control a neuron's capacity to adapt to imbalances in network activity and synaptic strength.
In this dissertation, I use the tools of functional genomics to investigate different homeostatic mechanisms at this model synapse and to characterize transcriptional diversity within Drosophila larval motor neurons. First, I demonstrate that specific loss of key proteins in synaptic transmission in motor neurons induces homeostatic compensation, which features an increase in activity and altered expression of proteins that contribute to neuronal firing. Second, I show that mutation of a gene involved in the organization of the muscular cytomatrix mimics a classic model of presynaptic homeostatic potentiation. This new model also has alterations in cell-adhesion molecules which may be causal for this mode of homeostasis. Finally, I characterize the transcriptional diversity of glutamatergic motor neurons in this system, revealing that the expression of ion channels and activity regulated genes is correlated with temporal identity.