The long-term goal of the lab is to understand the cellular and molecular mechanisms that govern synaptic growth and plasticity, and how dysfunction in these pathways contributes to disease. Neurons are the most morphologically diverse cell type whose morphology determines many functional aspects of a neuronal network. The primary shape of a neuron is established during axon and dendrite outgrowth and synapse formation, but is subject to subsequent modifications by physiological events. In response to changes in synaptic activity, neurons can alter both pre and postsynaptic elements of the synapse. The process by which neurons change their shape in response to activity is called structural plasticity. Postsynaptic compartments, such as dendritic spines or the postsynaptic membrane of the Drosophila neuromuscular junction (NMJ) (called the subsynaptic reticulum or SSR), are highly dynamic elements that are subject to this type of plasticity. While it is known that the shape of postsynaptic structures is tightly coupled to synaptic function, the factors that govern the morphology and its relationship with functional plasticity are almost entirely unknown. We have recently uncovered a novel mechanism that regulates the expansion of postsynaptic membranes in response to synaptic activity. We found that the exocyst complex, a tethering complex conserved from yeast to human, is the target of a Ca2+ and Ral-dependent pathway that converts signals from synaptic activation into membrane growth and consequent anatomical plasticity at the Drosophila NMJ (Figure 1). By being able to receive regulatory information from different pathways, the exocyst can serve as a hub to precisely regulate where and when vesicles fuse. Defects in synaptic morphology and in activity-dependent plasticity are a hallmark of several neurodegenerative and cognitive disorders. It is therefore critical to know the basic mechanisms by which neurons acquire their shape and change it in response to activity, and to dissect the genes that regulate these processes. To address these, our objectives are:
1) To dissect the pathway(s) downstream of postsynaptic Ral/exocyst activation?
2) To understand the physiological consequences of morphological changes of the SSR?
3) To uncover novel regulators of neuronal membrane trafficking.
Our strategy is to use the Drosophila NMJ as a model because it is a highly plastic glutamatergic synapse, with stereotypical morphology that is genetically determined, but that can be remodelled by synaptic activity. In addition to the powerful genetics and other available tools for the study of Drosophila synapses, 75% of all human disease genes have related sequences in Drosophila and nearly a third are predicted to have functionally equivalent counterparts, making Drosophila an excellent model to study these questions.
Figure 1. Model of Ral and Exocyst involvement in an activity-driven pathway for postsynaptic membrane addition.
- Silva-Rodrigues JF, Patrício-Rodrigues CF, de Sousa-Xavier V, Augusto PM, Fernandes AC, Farinho AR, Martins JP, Teodoro RO. Peripheral axonal ensheathment is regulated by Ral GTPase and the exocyst complex. Development 2020 : dev.174540 doi: 10.1242/dev.174540 Published 22 January 2020
- Patrício-Rodrigues, C. F., & Teodoro, R. O. (2018). Postsynaptic Rab GTPases and Exocyst: a screen at the Drosophila neuromuscular junction. Sciencematters.Io. http://doi.org/10.19185/ma
- Teodoro RO*, Pekkurnaz G, Nasser A, Higashi-Kovtun ME, Balakireva M, McLachlan IG, Camonis J and Schwarz TL* (2013). Ral mediates activity-dependent growth of postsynaptic membranes via recruitment of the exocyst. EMBO J. Jul 17, 32(14):2039-55.
* Corresponding Authors
- Murthy M*, Teodoro RO*, Miller TP, Schwarz TL (2010). Sec5, a member of the exocyst complex, mediates Drosophila embryo cellularization. Development 137(16):2773-83.
* Equal 1st Author Contribution.
- Teodoro RO and O’Farrell PH (2003). Nitric oxide-induced suspended animation promotes survival during hypoxia. EMBO J. 22, 580-587.
(Editor’s choice, Science Feb 14 2003: 979)