Hearing function. (A) Representative ABR recordings in response to click stimuli of wild-type, Irs2−/−Ptpn1+/+ and Irs2−/−Ptpn1−/− mice at 5 (upper row) and 11 (bottom row) wks of age. IRS2-deficient mice showed profound deafness compared with the normal ABR pattern of the wild-type mice, at both ages studied. Double-null mice developed severe hearing loss during the time window studied. (B) ABR thresholds (mean ± standard error of the mean [SEM]) in response to click stimuli in wild-type (□), Irs2−/−Ptpn1+/+ (■), Irs2+/+Ptpn1−/− (▤) and Irs2−/−Ptpn1−/− (▥) mice, at both ages studied. Wild-type and Irs2+/+Ptpn1−/− mice maintained normal hearing thresholds during the study. Statistically significant differences were found between IRS2-deficient mice and normal hearing genotypes at both ages (***P < 0.001), whereas double-null mice presented significantly raised thresholds only in adulthood (###P < 0.001). (C) ABR thresholds in response to tone burst stimuli (8–40 kHz) in wild-type (○), Irs2−/−Ptpn1+/+ (●), Irs2+/+Ptpn1−/− (▲) and Irs2−/−Ptpn1−/− (■) at both ages studied. Irs2-null mice showed an all-frequency involved hearing loss, with statistically significant differences compared with wild-type (***P < 0.001) and Irs2+/+Ptpn1−/− mice, which maintained normal thresholds throughout the study. The lack of PTP1B in Irs2−/−Ptpn1−/− mice delayed and tempered the increase of the audiogram with statistically significant differences, with control mice appearing only in the adult age (###P < 0.001). Thresholds for 4 and 40 kHz were significantly lower in double-null mice compared with Irs2−/−Ptpn1+/+ mice (†P < 0.05). (D) Scheme of the auditory pathway, indicating the main structures and the correspondence with ABR peaks. Cochlear ganglion neurons connect with the cochlear nuclei, which project into the lateral lemniscus via acoustic striae and afterwards in the nucleus of the inferior colliculus. Neurons in the inferior colliculus project to the medial geniculate body of the thalamus that sends tonotopical projections to the primary auditory cortex. Several accessory auditory brain stem nuclei send both crossed and uncrossed projections through the lateral lemniscus.