Synapses are specialized cell-cell junctions of the central nervous system (CNS) that are critical for learning, memory, and cognition. Localized to these junctions are cell adhesion molecules (CAMs) that link the presynaptic axon with the postsynaptic dendrite, which establish synaptic structure and function. CNS synapses are now considered a three-membered entity, or tripartite synapse, which include the axon terminal, the dendrite, and an ensheathing astrocyte process. Astrocytes are non-neuronal, architecturally complex cells with branches that terminate in thousands of fine processes that interact with synapses. A single mouse astrocyte can contact more than 100,000 synapses at a time. While decades of research have identified how synapses between two neurons are formed, the molecular mechanisms that regulate astrocyte-synapse interactions remain elusive. Additionally, the mechanisms and molecular links between astrocyte morphology and synapse association are unknown. Astrocyte branching complexity develops in the rodent cortex during the second postnatal week, a time of significant excitatory synapse formation. In preliminary experiments I found that astrocytes in vitro require contact with neurons to establish a complex morphology. Because astrocytes specifically contact synapses, it is likely that astrocytes express CAMs to interact with these neuronal adhesions. In preliminary experiments, I discovered that astrocytes express the neuroligin (NL) family of CAMs, which are known to play critical roles at neuronal synapses, and previously thought to be functional only in neurons. NLs are well-studied molecules that regulate synapse formation and structure of dendritic trees. Knockdown of astrocytic NLs in culture by shRNA demonstrated that NLs are required for establishing astrocyte morphology in response to neuronal contact. These data are novel and indicate that there are previously unknown functions of NLs in astrocytes, which potentially link astrocytes to synapses and control complex astrocyte architecture. Based on these observations and previously published results this proposal will utilize novel and well- established techniques to determine how NLs in astrocytes regulate synapse interaction and generate astrocyte architectural complexity. By combining cell biology, light and electron microscopy, and electrophysiology, the aims of this proposal will test the structural and functional requirement of NLs in astrocytes and identify the molecular mechanisms of astrocyte-neuron contact and downstream signaling through astrocytic NLs. The outcomes of this proposal will open exciting new avenues in studying the interactions between neurons and astrocytes throughout development and neural plasticity. NLs are associated with a number or disease states including autism and epilepsy. Therefore the proposed work will illuminate the need for reevaluation of these CAMs within the entirety of the tripartite synapse.
As a result of this work, I anticipate to provide novel information about the dynamic relationship between astrocytes and synapses, which may regulate brain disorders, such as autism and epilepsy. Manipulation of astrocyte-synapse interactions may provide a novel avenue for treating neurological disorders and improving learning and memory.
|Stogsdill, Jeff A; Eroglu, Cagla (2017) The interplay between neurons and glia in synapse development and plasticity. Curr Opin Neurobiol 42:1-8|
|Stogsdill, Jeff A; Ramirez, Juan; Liu, Di et al. (2017) Astrocytic neuroligins control astrocyte morphogenesis and synaptogenesis. Nature 551:192-197|
|Singh, Sandeep K; Stogsdill, Jeff A; Pulimood, Nisha S et al. (2016) Astrocytes Assemble Thalamocortical Synapses by Bridging NRX1? and NL1 via Hevin. Cell 164:183-196|