- Critical interactions between neurons and glial cells in the developing nervous system
- Roles of glial cells in synaptic modulation
- Functional organization and plasticity of olfactory systems
- Use of insect nervous systems as tractable experimental systems that provide broad insights into neuron-glia interactions
Research in my laboratory for many years focused on the development and functional organization of the olfactory system, studied in a convenient model organism, the moth Manduca sexta. Our work yielded strong evidence for critical roles for glial cells in creating glomerular architecture. More recently, we have shifted our focus to the fruit fly Drosophila melanogaster, where we are exploring the roles of glial cells in supporting and modulating mature neural function.
The lab is co-directed by my long-standing colleague and collaborator, Research Professor Lynne Oland.
Development of the olfactory pathway. Over the years, our research has been aimed primarily at elucidating key intercellular interactions during development of the olfactory system. We have been especially interested in the mechanisms underlying the wide-spread phenomenon that sensory neurons guide many aspects of development in their target areas in the brain. Using the olfactory system of Manduca, we found in 1987 that glial cells must be present in order for the axons of olfactory receptor neurons, whose cell bodies are located in the antenna, to induce the formation of synaptic glomeruli in the antennal (olfactory) lobes of the brain.
Much of our work since then has built on the working hypothesis that glial cells act as essential intermediaries in the developmental influence that olfactory axons exert upon their targets - i.e. that glial cells, which are induced by axons to surround developing synaptic glomeruli, form a necessary scaffold within which receptor neurons and target neurons subsequently differentiate their glomerular arbors. We discovered that neuronal activity is not necessary for the formation of a glomerular architecture, so we have focused our attention on cell-surface and extracellular signaling molecules, such as fasciclin II, epidermal growth factor receptors, tenascin, and nitric oxide, that appear to be involved.
We also have studied molecular mechanisms of axon guidance, as we seek to understand how olfactory receptor axons find their correct glomerular targets in the antennal lobe, to produce circuitry that can encode olfactory stimuli. In 1999, we discovered a glia-rich "sorting zone" for axons in the antennal nerve, and, using methods that deplete the developing system of glial cells, we found over subsequent years that those glial cells must be present for sensory axons to sort properly.
Neuron-glia interactions that modulate neuronal function. In recent years, we have been using Drosophila melanogaster for molecular genetic investigations of neuron-glia interactions that go beyond the interactions we have explored in Manduca. Fundamentally, we are asking how glial cells in the ventral nerve cord modulate activity in particular neurons.
Using whole-cell electrophysiological recordings from Drosophila astrocytes, we have characterized the intrinsic properties of those cells as well as their physiological relationships with particular premotor synapses. Intrinsic electrical properties were found to be strikingly similar to those of vertebrate astrocytes. Analysis of astrocyte responses to optogenetic stimulation of glutamatergic premotor neurons revealed bidirectional neuron-glia communication involving the excitatory amino acid transporter 1 (Eaat1) in astrocytes. In collaboration with the group of Albert Cardona at the HHMI Janelia Research Campus, we used serial electron microscopy reconstructions to discover that, although they are not ensheathed by glial processes, neuronal synapses in that particular premotor system were always located within 1 micron of an astrocytic process. Thus, fly astrocytes can modulate fast synaptic transmission via neurotransmitter transport even in the absence of strict tripartite-synapse ensheathment.
We currently are using several molecular genetic approaches to generate stochastic labeling of glial cells, so that we can analyze the branching patterns and tiling arrangement of astrocytes in the neuropil of the ventral nerve cord in normal flies and in flies with altered neural activity.
In the long run, we will continue to enhance knowledge of the intercellular interactions between developing and mature neurons and glial cells at structural, functional, and molecular levels. We expect that the knowledge we gain will continue to offer insights into intercellular influences in less accessible mammalian systems.
MacNamee SE, Liu SE, Gerhard S, Tran CT, Fetter RT, Cardona A, Tolbert LP, Oland LA (2016) Astrocytic glutamate transport regulates a Drosophila CNS synapse that lacks astrocyte ensheathment. J Comp Neurol 524:1979-98.
Gibson NJ, Tolbert LP, Oland LA (2012) Activation of glial FGFRs is essential in glial migration, proliferation, and survival and in glia-neuron signaling during olfactory system development. PLoS ONE 7(4):e33828.
Oland LA, Tolbert LP (2011) Role of glial cells in neural circuit formation: Insights from research in insects. Glia 59:1273-1295.
Koussa MA, Tolbert LP, Oland LA (2010) Development of a glial network in the olfactory nerve: role of calcium and neuronal activity. Neuron Glia Biol. 6:245-261.
Oland LA, Gibson NJ, Tolbert LP (2010) Localization of a GABA transporter to glial cells in the developing and adult olfactory pathway of the moth Manduca sexta, J Comp Neurol. 518(6):815-838.
Gibson NJ, Tolbert LP, Oland LA (2009) Roles of specific membrane lipid domains in EGF receptor activation and cell adhesion molecule stabilization in a developing olfactory system, PLoS One. 4(9):e7222.
Oland LA, Biebelhausen JP, Tolbert LP (2008) Glial investment of the adult and developing antennal lobe of Drosophila, J Comp Neurol. 509(5):526-550.
Gibson NJ, Tolbert LP (2006) Activation of epidermal growth factor receptor mediates receptor axon sorting and extension in the developing olfactory system of the moth Manduca sexta, J Comp Neurol. 495(5):554-572.