Background:
Brain networks are formed during development and consist of neurons and glial cells that constantly exchange information, transmitting signals from one area to the other. Early disruptions in network function are observed in autism spectrum disorders (ASDs) and lead to the appearance of symptoms that persist into adulthood. Myelination, the formation of a multi-layered membrane around axons by oligodendrocytes in the central nervous system, accelerates signal transmission and shapes network performance. In human ASD brains the volume of myelinated axons is often reduced, while several rodent models of ASDs show dysregulations of myelin genes and delays in developmental myelination (1-3).
What is the effect of ASD-related genetic mutations on the ability of the oligodendrocyte to myelinate different axons and how does that impact neuronal function? Are these myelin defects a point of convergence between ASDs that can be targeted to restore function?
Rationale & hypothesis:
The process of myelination starts around birth and peaks during the first post-natal weeks in rodents. During this period, mature oligodendrocytes extend processes that can myelinate both excitatory and inhibitory axons forming various patterns of myelination in the cortex that will affect the speed and the fidelity of signal transmission (4). Our preliminary data show that the myelination of inhibitory interneurons is reduced in the cortex of Fragile X model rats, one of the most common monogenic forms of ASD. Given that many of the genes that are responsible for the development of ASDs are also expressed by oligodendrocytes we hypothesize that:
The ASD-related genetic mutations disrupt the normal myelination of cortical axons during development and contribute to the network dysfunction we see in ASDs.
Aims: This project aims to:
Training outcomes: Techniques of this project include:
Isolation and culture of rat and mouse oligodendrocytes, oligodendrocyte-neuron co-cultures, ex vivo organotypic slices, electrophysiology, in vivo transplantation of oligodendrocyte precursors in the brain, Immunofluorescence and confocal microscopy, molecular biology, and biochemistry techniques, data acquisition and analysis, manuscript preparation.
