Dysregulation of synapses is thought to underlie a range of neurological disorders, and astrocytes are key mediators of synaptic maintenance, formation and elimination. Neurons form more synapses when co- cultured with astrocytes, and a single astrocyte may ensheath 100,000 synapses in vivo. This critical role led to the ?tripartite synapse? model: the synapse is not only comprised of the presynaptic bouton and postsynaptic density but also includes a peripheral astroglial process(PAP). Like dendrites and boutons, the PAP has a specific protein composition and is remodeled morphologically in response to local activity. Extensive work has demonstrated that synaptic remodeling is regulated by local translation in neurons, particularly in the dendrite. Specific mRNAs are shuttled into dendrites where their translation can be stimulated by a variety of extracellular signals, allowing for fine-tuned regulation of local protein synthesis. Newly synthesized proteins are thought to mediate the strengthening of individual synapses that underlies learning and memory, as inhibiting translation also inhibits formation of memory. As both PAPs and dendrites are remodeled in response to activity, it is likely that both responses are essential to increasing the overall efficacy of individual synapses in response to experience. Thus a key question in the field is are astrocytes, like neurons, also able to localize specific mRNAs to their processes for translation? Here, we will address this question using biochemical approaches and functional assays to test for the enrichment and translation of specific mRNAs in the PAP. We will seek to: 1) identify the transcripts localized to astroglial ribosomes in processes, 2) determine whether features in the sequence of the transcripts themselves mediate their local translation in astrocytes, 3) determine whether molecular cues of neuronal activity are capable of stimulating local translation in astrocytes.
Disorders such as autism, Fragile X syndrome, and other forms of intellectual disability are thought to involve dysregulation synapses in the brain. Learning entails the strengthening of individual synapses of neurons, and this is known to involve the generation of new proteins locally where they are needed in the neurons. It is now known that for neurons to efficiently make synapses, they need the support of cells called astrocytes, which provide fine processes wrapping the synapses. We are testing whether astrocytes, like neurons, have the ability to make new proteins locally in these processes to help improve the efficiency of the synapses.
