Autism spectrum disorders (ASDs) are a broad spectrum of conditions characterized by impairments in social interactions and communication, as well as restricted and repetitive behaviors. Neural circuit dysfunction in ASD has been well studied with respect to synaptic alterations. More recently, white matter aberrations have come to light in people with ASDs, suggesting that dysregulation of myelination may contribute to ASD pathophysiology.
Michelle Monje’s group and others have shown that neuronal activity regulates the dynamics of myelin-forming cells and mediates the adaptation of myelin to experience1. The connections between neurons and oligodendrocyte precursor cells (known as ‘axon-glial synapses’) are thought to play an important mechanistic role in neuronal activity regulated myelin plasticity. Disruption or aberrations in axon-glial synapses could dysregulate myelin plasticity. Monje’s group previously showed that the synaptic protein neuroligin 3 is cleaved and shed from oligodendrocyte precursor cells in an activity-dependent manner in the healthy brain2, suggesting a role for neuroligin 3 in myelination.
The field currently lacks a clear understanding of the role that alterations in myelin or myelin plasticity may play in ASD pathophysiology. Here, Monje proposes to study myelin and neuronal activity-regulated myelin plasticity in a neuroligin 3 mutant mouse model of ASD. Monje will focus on the ASD-associated mutation Nlgn3(R451C) as an initial step to explore myelin integrity and plasticity in ASD. Monje’s team aims to understand how this mutation affects oligodendroglial lineage dynamics and myelin plasticity in ASD-related neural circuits.
Firstly, they will assess myelin integrity and myelin-forming cell dynamics in Nlgn3(R451C) knock-in mice using both florescent and electron microscopy techniques. Next, they will establish whether there is a failure in adaptive responses in myelin-forming cell dynamics, which might cause neural circuit alterations, using optogenetic stimulation of neuronal activity and subsequent evaluation of activity-regulated myelin changes. Together, the proposed studies may begin to elucidate an understudied aspect of ASD pathophysiology.