Role of SCN2A in Myelination and Neural Circuit Development in Autism Spectrum Disorder

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ABSTRACT Auditory processing abnormalities are common and prominent features of neurodevelopmental disorders such as autism spectrum disorder (ASD). A central challenge of autism research is to identify common mechanisms that underlie sensory processing abnormalities including auditory dysfunction. One prevalent hypothesis is that the behavioral phenotypes in ASD arise from altered functional connectivity in the brain. Neuroimaging studies and the transcriptional profile in human ASD indicate that altered myelination and white matter integrity could be a common pathophysiology that impairs functional connectivity. Auditory processing requires precise and timely control of axonal conduction and synaptic activity, making the auditory system vulnerable to the developmental disruptions of ASD. Our long-term goal is to investigate the mechanisms whereby altered myelination and brain connectivity impair auditory processing in neurodevelopmental disorders. Our previous studies have shown that alterations in myelination disrupt axonal conduction, alter synaptic function, and impede circuit-level functions in the auditory brainstem. Our recent studies pioneered a new concept in how excitability in oligodendrocytes (OL), the myelinating glial cell, contributes to communication between neurons and OLs. We characterized a subpopulation of excitable OLs that express the voltage-gated Na+ channel 1.2 (Nav1.2), display Nav1.2- mediated spiking, and respond to neuronal activity. Notably, Scn2a, which encodes the alpha subunit of Nav1.2 channel, has a robust association with ASD. These studies indicate that oligodendroglial Scn2a is important for electrical excitability in OLs, for communication between OL and neurons, and for establishing functional connectivity in the auditory brainstem. The primary objective of the proposed study is to link the loss of oligodendroglial Scn2a to alterations in myelination and neural connectivity in the auditory system to better understand how auditory processing is altered in Scn2a-mediated disorders and ASD. We have generated a novel Scn2a conditional knockout mouse (cKO) to specifically delete Scn2a in OLs. These mice exhibit deficits in myelination, altered neurotransmission, and remarkable changes in auditory function. We hypothesize that Scn2a expression in developing OLs is required for coordinating neuron-OL interactions that are essential for myelination and proper development of neural circuits in the auditory nervous system. Using multiple-approaches including in vivo and in vitro electrophysiology, we will determine the role of Scn2a in OL development and myelination (Aim 1), examine how the loss of Scn2a-expressing OL alters synaptic transmission and plasticity at a local synapse in the auditory brainstem (Aim 2), and link the loss of oligodendroglial Scn2a to alterations neural connectivity and auditory processing abnormalities (Aim 3). In summary, this study will reveal how loss of Nav1.2-mediated OL excitability alters myelination, functional connectivity, and auditory processing in the auditory brainstem. Understand how altered myelination results in neural circuitry dysfunction that functionally related to auditory processing abnormalities in a novel model will provide better therapeutic strategies for ASD.