Hearing loss promotes schizophrenia-relevant brain and behavioral abnormalities in a mouse model of human 22q11.2 Deletion Syndrome

ABSTRACTHearing loss has been implicated as a risk factor for schizophrenia, but it is not known whether this association arises from common etiology, top-down influences (e.g., social isolation), bottom-up neurobiological mechanisms, or combinations of these factors. Patients with 22q11.2 Deletion Syndrome (22q11.2DS) have a 25-30% risk of developing schizophrenia, and also suffer frequent hearing loss. Here, we used the Df1/+ mouse model of 22q11.2DS to investigate the relationship between hearing loss and susceptibility to schizophrenia-relevant brain and behavioral abnormalities. Df1/+ mice have a multi-gene deletion analogous to the chromosomal microdeletion that causes human 22q11.2DS, and like human 22q11.2DS patients exhibit high rates of hearing loss arising primarily from susceptibility to middle ear inflammation. We found that hearing loss in Df1/+ mice affected schizophrenia-relevant endophenotypes, including electrophysiological measures of central auditory gain and behavioral measures of auditory sensorimotor gating. Moreover, PV+ inhibitory interneurons, another marker for schizophrenia pathology, were significantly reduced in density in auditory cortex but not secondary motor cortex of Df1/+ mice with hearing loss. These results reveal bottom-up neurobiological mechanisms through which peripheral hearing loss arising from the 22q11.2 deletion may promote the emergence of schizophrenia-relevant auditory brain and behavioral abnormalities, and also suggest a link between conductive hearing loss and reduced PV+ interneuron density in the auditory cortex.SIGNIFICANCE STATEMENTHearing loss is a known risk factor for schizophrenia. Deletion of chromosomal locus 22q11.2 is associated with both schizophrenia and hearing loss in humans. In the Df1/+ mouse model of human 22q11.2 Deletion Syndrome, we find that hearing loss shapes measures that are considered schizophrenia-relevant endophenotypes, such as central auditory gain and auditory sensorimotor gating. Moreover, we report a reduction in density of PV+ inhibitory interneurons in the auditory cortex, but not secondary motor cortex, of Df1/+ mice with hearing loss. These results suggest mechanisms through which hearing loss associated with the 22q11.2 deletion may promote emergence of schizophrenia-relevant auditory brain and behavioral abnormalities and indicate that conductive hearing loss may influence PV+ interneuron density in the auditory cortex.