Neuronal circuit function and behaviour require communication between neurons and glia in the central nervous system (CNS). CNS glia called oligodendrocytes (OLs) form myelin sheaths that insulate axons, enabling them to propagate action potentials much faster than unmyelinated axons. Early in postnatal development, different patterns of axonal myelination arise that depend on axonal geometry and neuronal identity. For instance, in mice the axons of excitatory neurons of the deep cortical layers are continuously myelinated but the axons of excitatory neurons of the superficial cortical layers are intermittently myelinated. Similarly, several subtypes of inhibitory neurons have more myelin than others and our recent work showed that myelin is critical for their function and integrity.
Neuronal activity dynamically modulates the myelination patterns throughout life. Recent evidence indicates neuron-type specific myelin dynamics in response to changes in neuronal activity. These activity-dependent myelin modulations are now considered a form of circuit plasticity that support cognitive functions such as learning and social interactions. In many neurodevelopmental disorders associated with autism spectrum disorder and intellectual disability (ASD/ID), these aspects of cognition are often altered. Recently, MRI, genome-wide association and transcriptomic studies including people with ASD/ID, human post-mortem tissue and ASD/ID animal models revealed a shared dysregulation of oligodendrocyte–specific genes and structural alterations in myelinated tracts, indicating that myelin disruption is a key phenotype in ASD/ID pathophysiology. Nevertheless, how myelin alterations contribute to the development of ASD/ID symptoms is unknown.
In humans, myelination starts around birth and increases sharply in the first years of life, concurring with the first manifestations of ASD/ID in children. Our working hypothesis is that changes in myelination during early postnatal brain development affect the physiological network function and contribute to the appearance of ASD/ID-related phenotypes.
We take advantage of the available mouse and rat models of syndromic forms of ASD/ID to investigate:
- How the ASD/ID- associated genetic mutations affect oligodendrocyte function and myelination of excitatory neurons and inhibitory interneurons.
- How myelination impairments affect neuronal function and behaviour.
- The effectiveness of systemic myelin-modulating drugs in restoring cellular, physiological and behavioural alterations in ASD/IDs.
To further unpick the myelin effects on neuronal and network dysfunction in syndromic ASD/ID, we develop genetic tools alter the levels of myelination in a neuron specific manner. Our overarching goal is to manipulate the altered mechanisms of neuron-oligodendrocyte interactions in ASD/ID with the hope to reveal alternative or complementary strategies for cellular and functional recovery in ASD/ID.