The role of astrocytes in inhibitory synaptogenesis

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DESCRIPTION (provided by applicant): The assembly of CMS synapses is a complex and dynamic process, requiring the coordinated exchange of signals between pre- and postsynaptic neurons and surrounding glia. Astrocytes, one type of glia, have been shown to increase the formation and function of excitatory synapses, in part by releasing soluble factors as well as by contact. However/the role that astrocytes play in inhibitory synapse formation and function has not been well studied. It is the goal of this proposal to examine the role of astrocytes in inhibitory synaptogenesis in the developing nervous system. Previous work from the Balice-Gordon lab and my preliminary studies in hippocampal neurons in vitro suggest that astrocytes release soluble signals into the media (astrocyte conditioned media, ACM) that increase inhibitory neuron axon elongation, branching as well as synaptogenesis, by the criteria of increasing the number of GABAergic presynaptic terminals co-localized with postsynaptic GABAAR clusters (Elmariah et a I.", 2005; Hughes et al., 2005). My preliminary studies also suggest that neuronal contact with astrocytes, but not ACM, increase the number of functional GABAergic synapses. This leads to the hypothesis that secreted and contact signals from astrocytes differentially mediate the formation and function of inhibitory synapses during neural development. To test this hypothesis, I will: (1) Determine how astrocyte soluble signals affect inhibitory axon outgrowth, branching and synaptogenesis in a series of experiments. (2) Examine the role of neuron- astrocyte contact in the development of inhibitory synapse function. (3) Identify soluble signals released by astrocytes that increase inhibitory axon outgrowth, branching and synaptogenesis. Taken together, these experiments will extend our understanding of how inhibitory synapses are formed during neural development. The results of these studies will extend our understanding of how neuron-glia signaling modulates synapse formation and function, and set the stage for defining the underlying cellular and molecular mechanisms. Understanding these mechanisms will provide a foundation of knowledge that may, in the future, suggest avenues for therapeutic intervention for disorders of development such as epilepsy, autism and mental retardation, in which synapse formation and/or function are aberrant or reduced.