Increased Central Auditory Gain and Decreased Parvalbumin-Positive Cortical Interneuron Density in the Df1/+ Mouse Model of Schizophrenia Correlate With Hearing Impairment

BACKGROUND: Hearing impairment is a risk factor for schizophrenia. Patients with 22q11.2 deletion syndrome have a 25% to 30% risk of schizophrenia, and up to 60% also have varying degrees of hearing impairment, primarily from middle-ear inflammation. The Df1/+ mouse model of 22q11.2 deletion syndrome recapitulates many features of the human syndrome, including schizophrenia-relevant brain abnormalities and high interindividual variation in hearing ability. However, the relationship between brain abnormalities and hearing impairment in Df1/+ mice has not been examined. METHODS: We measured auditory brainstem responses, cortical auditory evoked potentials, and/or cortical parvalbumin-positive (PV(+)) interneuron density in over 70 adult mice (32 Df1/+, 39 wild-type). We also performed longitudinal auditory brainstem response measurements in an additional 20 animals (13 Df1/+, 7 wild-type) from 3 weeks of age. RESULTS: Electrophysiological markers of central auditory excitability were elevated in Df1/+ mice. PV(+) interneurons, which are implicated in schizophrenia pathology, were reduced in density in the auditory cortex but not the secondary motor cortex. Both auditory brain abnormalities correlated with hearing impairment, which affected approximately 60% of adult Df1/+ mice and typically emerged before 6 weeks of age. CONCLUSIONS: In the Df1/+ mouse model of 22q11.2 deletion syndrome, abnormalities in central auditory excitability and auditory cortical PV(+) immunoreactivity correlate with hearing impairment. This is the first demonstration of cortical PV(+) interneuron abnormalities correlating with hearing impairment in a mouse model of either schizophrenia or middle-ear inflammation.