Autism Spectrum Disorders and Auditory System Deficits: Role of Neuronal and Immune System Dysfunction

ABSTRACT Hearing impairment in children with autism spectrum disorders (ASDs) may contribute to core ASD symptoms by interfering with language development and communication. The number of individuals with ASD or other neurodevelopmental disorders is growing rapidly, thus studies are urgently needed to address how and to what

extent auditory system deficits are associated with ASD-like behaviors. Mounting evidence supports the hypothesis that peripheral auditory system deficits reflective in auditory nerve dysfunction may contribute to the pathophysiological changes observed at the cortical level (e.g., hyperacusis or other auditory processing

deficiencies). However, the lack of mechanistic studies using translational animal models of ASD with well- characterized auditory functional impairments is a critical barrier to uncovering potential relationships and causal links between structural and functional auditory deficits and ASD-related behaviors. Mutations or

deletions in the Myocyte-specific Enhancer Factor 2C (MEF2C) gene have been linked to ASD and other neurodevelopmental disorders in humans. Our recent studies using a mouse model of human MEF2C haploinsufficiency syndrome (MCHS) revealed that Mef2c deficiency leads to altered neural activity in the cortex, increased microglial activation, and deficits in communication, social interaction, and other MCHS

symptoms that are characteristic of ASD. Using this mouse model, our studies also show (1) that Mef2c may play a role in the development and function of spiral ganglion neurons of the auditory nerve and regulation of cochlear macrophage activity, (2) an important association between Mef2c deficiency and auditory nerve

dysfunction, and (3) that Mef2c deficiency leads to cortical neural dysfunction in response to auditory stimuli. Together these exciting data support the hypothesis that ASD risk-gene MEF2C deficiency in spiral ganglion neurons and macrophages can lead to auditory nerve dysfunction and increased macrophage activation, which

in turn contributes to auditory cortical dysfunction and core symptoms of ASD. This multiple PI proposal will test this novel hypothesis using a multidisciplinary approach. The proposed experiments will characterize unique temporal and spatial expression patterns of Mef2c in both spiral ganglion neurons and cochlear

macrophages that are associated with auditory nerve development and maintenance (Aim 1), determine the causal links between Mef2c deficiency-induced auditory nerve dysfunction and auditory cortical dysfunction, and core symptoms of ASD (Aim 2), and test the extent to which inhibition of abnormal macrophage activation

ameliorates auditory nerve dysfunction, auditory cortical dysfunction, and core ASD symptoms (Aim 3). These investigations will promote a greater understanding of the important role of immune cells and auditory system deficits in ASD and possible other neurodevelopmental disorders and may reveal a neuro-immune-based

therapeutic strategy beneficial for this increasingly common disorder.