Axon selection for myelination by excitatory postsynaptic factors

PROJECT SUMMARY Myelin, produced by oligodendrocytes (OLs), is a specialized lipid-rich membrane critical for rapid electrical signal transmission in the central nervous system. OLs are uniquely positioned to modulate circuit activity as they can myelinate up to 40 axons simultaneously, while also differentially distributing myelin on individual axons. Yet how oligodendrocytes select axons for myelination has only recently started to be explored. Our lab has shown that neuronal activity promotes and stabilizes myelin sheath formation and that synaptic vesicle release occurs along axons underlying nascent myelin sheaths. Together, this suggests an intricate mechanism of communication, where oligodendrocytes receive myelination promoting signals from axons. Interestingly, we have found that in OLs, postsynaptic scaffolding and adhesion proteins occupy nascent sheaths and regulate myelin sheath characteristics. Most recently, work from our lab has shown that OLs use specific postsynaptic proteins to myelinate axons based on their neurotransmitter identity. Specifically, we found that the canonical postsynaptic scaffolding protein Gephyrin is enriched in myelin of inhibitory GABAergic and glycinergic axons, functioning to select and regulate the distribution of myelin to these axon classes. If inhibitory postsynaptic proteins guide the myelination of inhibitory axons, do excitatory postsynaptic proteins guide the myelination of excitatory neurons? I hypothesize that the excitatory postsynaptic protein PSD-95 regulates the myelination of glutamatergic neurons by coordinating localization of adhesion molecules. In this proposal, I will utilize genetic manipulation and in vivo and fixed light microscopy in zebrafish to test this hypothesis via two aims. Aim 1 tests if the canonical excitatory scaffolding protein PSD-95 selects and coordinates myelin distribution on glutamatergic axons. Aim 2 tests if PSD-95 regulates myelination by coordinating the localization of excitatory postsynaptic cell adhesion molecules.