Developmental characterization of synapses between neurons and oligodendrocyte precursor cells

Synaptic connections between neurons are fundamental computational units in the brain that contribute to virtually all neurological functions. For this reason, synapses have been extensively characterized across structural, functional, and molecular levels, revealing insights into the mechanisms through which synapses are established during brain development and deepening our understanding of how impairments in synaptic maturation contribute to autism and related disorders. Nevertheless, our ever-growing understanding of synapses has yet to give rise to effective pharmacological strategies for treating neurodevelopmental conditions. One reason for this lack of progress is that the specific population(s) of synapses that are affected in autism, and the precise ways in which their development goes awry, remain to be defined. Though synapses are widely considered to be the sole domain of neurons, seminal work in the early 2000s demonstrated that neurons also form functional synaptic connections with oligodendrocyte precursor cells (OPCs), a highly proliferative population of glia that makes up about 5% of the brain. OPCs express the requisite neurotransmitter receptors and signaling modules necessary to receive, interpret, and respond to synaptic innervation, and neuron-OPC synapses have been suggested to influence a range of functions including but extending beyond myelination. Yet, despite our relatively deep understanding of synaptic communication between neurons, synapses between neurons and OPCs remain poorly understood across all levels of analysis. Intriguingly, among all brain cells, OPCs are the highest expressers of synaptic adhesion molecules in the Neuroligin family, key mediators of synapse development that are among the strongest genetic drivers of autism risk. This observation raises the possibility that, despite the predominant view that impairments in the development of neuron-neuron synapses underlie autism, deficits in the development of neuron-OPC synapses could contribute as well. However, almost nothing is known about the mechanisms through which neuron-OPC synapses are assembled and refined in the contexts of either health or disease. In this application, we propose to examine the development of neuron-OPC synapses by harnessing the retinogeniculate pathway of the mouse visual system as a model for interrogating postnatal circuit refinement. In Aim 1, we will employ anatomical and electrophysiological approaches to map the maturation of synapses between neurons in the retina and OPCs (or neighboring relay neurons) in the visual thalamus in the presence or absence of OPC-expressed Neuroligins 1-3. In Aim 2, we will employ a proteomic screen to define the molecular composition of neuron-OPC synapses during development in an unbiased manner. Given that neuron- OPC synapses are the only synapse class through which neurons communicate directly with glia, virtually any insights into the development of neuron-OPC synapses will represent a significant advance for the field, and may inform new therapeutic strategies for treating disorders of brain development. Project Number: 1R21MH140036-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: Lucas Cheadle | Institution: COLD SPRING HARBOR LABORATORY, COLD SPRING HARBOR, NY | Award Amount: $528,000 | Activity Code: R21 | Study Section: Cellular and Molecular Biology of Glia Study Section[CMBG] View on NIH RePORTER: https://reporter.nih.gov/project-details/11291912