Myelination Deficits Underlying Auditory Issues in Fragile X Syndrome

Oklahoma State University Stillwater, Stillwater OK

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Abstract

Autism spectrum disorder (ASD) is characterized by an inability to function in environments with multiple competing sound sources, such as a noisy classroom. These auditory issues likely originate early in sound location processing that occurs in the brainstem. The projections that make up the auditory brainstem circuit that processes binaural (information from both ears) temporal, and intensity differences require heavily myelinated axons that convey precise information accurately from the cochlea to the brain. Our previous funded R15 showed decreased myelin thickness and axon fiber diameter in Fragile X Syndrome (FXS) mice, a monogenic form of ASD. We also showed a decrease in the latency of binaural waves in the auditory brainstem response (ABR), a non-invasive electrophysiological recording of this circuit, in FXS mice compared to controls. Lastly, animals have increased latencies to respond to reflexive auditory behavioral stimuli in FXS mice compared to controls. These data suggest that myelination deficits may underly binaural hearing difficulties in FXS, and perhaps ASD. We propose to further characterize myelination deficits in FXS using genetic approaches complemented with anatomical, physiological, and behavioral measures of myelination (microscopy, ABRs, and prepulse inhibition of the acoustic startle response). Primarily we are interested in understanding if myelination deficits we characterized in the original R15 are specifically due to loss of Fragile X messenger ribonucleoprotein (FMRP), the protein lacking in FXS, in neurons or in the myelinating glial cells (oligodendrocytes – OLs). We will use conditional knockout (cKO) or knockin (cKI) Fmr1 mice combined with Math5-cre, a cell type specific neuronal driver for auditory brainstem neurons, or MOBp a driver for OLs. We will then test animals on previously characterized auditory brainstem-specific tasks and approaches listed above to tease apart neuronal versus glial FMRP effects. Results from this study will determine how myelination contributes to binaural hearing processing issues in FXS and whether these deficits are specific to FMRP function in neurons or OLs. Lastly, we will use the same cKO and cKI animals and inject a viral vector with cre to express FMRP during specific time points to show when FMRP is acting in this circuit. All of the above experiments are approachable for undergraduate researchers thus funding from NIH increase student’s knowledge and ability to conduct basic research in line with the goals of the AREA program.